Mitochondrial contact sites are specialized interfaces where mitochondria physically interact with other organelles. Stabilized by molecular tethers and defined by unique proteomic and lipidomic profiles, these sites enable direct interorganellar communication and functional coordination, playing crucial roles in cellular physiology and homeostasis. Recent advances have expanded our knowledge of contact site-resident proteins, illuminated the dynamic and adaptive nature of these interfaces, and clarified their contribution to pathophysiology. In this Cell Science at a Glance article and the accompanying poster, we summarize the mitochondrial contacts that have been characterized in mammals, the molecular mechanisms underlying their formation, and their principal functions.

See supplementary information for a high-resolution version of the poster.

See supplementary information for a high-resolution version of the poster.

Close modal

In the 1950s, the association between mitochondria and the endoplasmic reticulum (ER) was first described (Bernhard et al., 1952; Bernhard and Rouiller, 1956), marking the beginning of the exploration of mitochondria–organelle membrane contact sites (MCSs), or mitochondria-associated membranes (MAMs), which are specialized areas where the outer mitochondrial membrane (OMM) is juxtaposed to the membrane of a different organelle, without fusion of the two heterotypic membranes. Two decades after their discovery, these initial observations of mitochondria–ER contacts were supported by biochemical evidence (Lewis and Tata, 1973; Shore and Tata, 1977), and in the 1990s their role in lipid and Ca2+ exchange was functionally annotated (Rizzuto et al., 1998; Vance, 1990). New techniques have helped to identify the protein–protein and protein–lipid interactions that facilitate the tethering of the two membranes, leading to the discovery and characterization of new mitochondrial contacts. Currently, mitochondria are considered ‘social’ organelles, communicating with almost every other organelle through physical contacts, which have been implicated in several cellular and pathophysiological processes (Perrone et al., 2020; Zung and Schuldiner, 2020).

The various interorganellar mitochondrial contacts can differ in number, length, protein composition and the distance of the gap between membranes, both among different cell types and among contacts in the same cell. Usually, the distance between two tethered membranes ranges from 10 nm to 80 nm, reaching over 300 nm in certain cases (Giacomello and Pellegrini, 2016). More than 5000 different proteins have been reported to reside in these compartments (Pan et al., 2024). These proteins fall into one or more of four major categories: tethers, which are proteins that physically bridge the two membranes; functional proteins, which facilitate specific functions at MAMs; regulator proteins, which influence the extent and distance of the contact site and/or the function of the other proteins residing there; and sorter or recruiter proteins, which affect the lipidome and proteome of the MAM (Scorrano et al., 2019). Table 1 lists some of the known functional proteins, regulators and sorting proteins found in mitochondrial MCSs. Although operational criteria have been identified to determine whether proteins residing at interorganellar interfaces function as tethers (Scorrano et al., 2019), defining molecularly whether such proteins are true tethers remains challenging. Measuring tethering forces is not straightforward, and many tethers and tethering complexes appear to be redundant, further complicating these types of analyses at the whole-cell level. Moreover, mitochondrial MCSs adapt to metabolic transitions and environmental cues (Casas-Martinez et al., 2024; Gordaliza-Alaguero et al., 2019), supporting the notion that they are dynamic structures that respond to changes in cellular function to regulate key processes.

Table 1.

Regulators of mitochondria–organelle contacts

Contact site proteinTethered organelleBinding partners (localization)Effect on contact structure and/or functionReferences
SERCA2 (ATP2A2) ER MFN2 (mit), calnexin (ER) Enhances MERCs (in tumor infiltrating CD8+ T cells). Regulates Ca2+ influx. Gutierrez et al., 2020; Yang et al., 2023  
STIM1 ER TMEM110 (also known as STIMATE) (ER) Increases contacts only upon ER Ca2+ depletion. Garcia Casas et al., 2024  
TESPA1 ER IP3R1 (also known as ITPR1) (ER), GRP75 (mit) Regulates Ca2+ flux. Matsuzaki et al., 2013  
TG2 (TGM2) ER BIP (ER), TOMM70 (mit), GRP75 (mit) Ablation decreases MERC number and alters composition but increases IP3R3 (ITPR3)–GRP75 interaction [in mouse embryonic fibroblasts (MEFs)]. Regulates Ca2+ flux. D'Eletto et al., 2018  
Miro1 and Miro2 ER SAMM50 (mit), MICOS (mit), TRAK1 and TRAK2 (cyt), VPS13D (mit) Double knockout decreases MERCs (in MEFs). Regulates mitochondrial Ca2+ signaling. Recruits VPS13D to mitochondria. Guillen-Samander et al., 2021; Modi et al., 2019  
BCL-2 ER IP3R (ER), CISD2 (ER) Overexpression decreases MERCs and inhibits Ca2+ transfer. Loncke et al., 2025; Namba et al., 2013  
BCL-2L10 ER IRBIT (also known as AHCYL1) (ER), IP3R (ER) Additive inhibition of IP3R with IRBIT. Bonneau et al., 2016  
IRBIT ER IP3R (ER) Upon apoptotic stress, inhibits BCL-2L10,
stimulates MERC formation, regulates
Ca2+ transfer and promotes apoptosis. 
Bonneau et al., 2016  
BOK ER IP3R (ER) Ablation decreases mitochondria–ER proximity and alters MAM composition (in MEFs). Regulates proper localization of MAM proteins, Ca2+ flux and apoptosis control. Carpio et al., 2021  
MCL1 ER BOK (mit) Regulates BOK targeting to MAMs. Increases contact number. Regulates apoptosis. Lucendo et al., 2020  
HK2 ER GRP75 (mit) Loosening of contacts (in HeLa cells). Regulates Ca2+ flux and calpain-dependent cell death. Ciscato et al., 2020  
CCDC127 ER VAPA (ER) Knockdown downregulates MERCs. Stabilizes VAPA. Xia et al., 2023  
PDK4 ER IP3R1 (ER), GRP75 (mit), VDAC1 (mit) Deletion diminishes MERC formation (in skeletal muscle, knockout mice). Increased activity induced by obesity augments MAMs (in C2C12 myoblasts, mouse muscle). Stabilizes the IP3R1–GRP75–VDAC1 complex. Thoudam et al., 2023; Thoudam et al., 2019  
Sigma1R (SIGMAR1) ER Ankyrin (cyt); BIP (ER); IP3R, upon ER Ca2+ depletion or ligand stimulation (ER); IRE1 (also known as ERN1), under ER stress (ER) Stabilizes IP3R. Prolongs Ca2+ release. Mediates stabilization of IRE1 and sensitization to mitochondria-derived ROS. Hayashi and Su, 2007; Joseph et al., 2018; Mori et al., 2013; Wu and Bowen, 2008  
DIAPH1 ER MFN2 (ER, mit) Decreases sarcoplasmic reticulum–mitochondrial distance via RAGE-induced interaction with MFN2 (in cardiomyocytes, endothelial cells, macrophages). Regulates Ca2+ handling, mitophagy and oxidative stress. Yepuri et al., 2023  
PERK ER ESYT1 (ER), Ero1a (ER) Depletion disrupts MERCs (in MEFs). Regulates
Ca2+ signaling, lipid transfer, apoptosis
induction, mitochondrial dynamics and
MERC protein oxidation. 
Bassot et al., 2023; Sassano et al., 2023; Verfaillie et al., 2012  
Ero1a ER IP3R (ER) Promotes oxidation of IP3R. Regulates Ca2+ fluxes. Anelli et al., 2012  
IRE1A ER IP3R (ER) Scaffold function. Regulates distribution of IP3R at MAMs. Promotes enhanced mitochondrial Ca2+ uptake. Carreras-Sureda et al., 2019  
FUNDC1 ER Calnexin (ER), DRP1 (mit), IP3R2 (also known as ITPR2) (ER) Ablation disrupts MAMs (in endothelial cells, neonatal cardiomyocytes). Regulates DRP1 recruitment at MAMs, mitochondrial fission, mitophagy in hypoxia and Ca2+ transfer. Wang et al., 2021a; Wu et al., 2017; Wu et al., 2016  
DRP1 ER MFF, FIS1, MiD49 (also known as MIEF2), MiD51 (also known as MIEF1) (mit); syntaxin 17 (ER); Shrm4 (also known as SHROOM4) (cyt) Promotes ER tubulation and mitochondrial fission. Upon starvation, syntaxin 17 switches its binding from DRP1 to ATG14 and facilitates the formation of autophagosomes. Stimulates formation of MERCs by promoting actin bundling and enhancing the traction anchoring between the ER and mitochondria. Adachi et al., 2020; Arasaki et al., 2015; Duan et al., 2023  
FIS1 ER BAP31, DRP1, syntaxin 17 Regulation of apoptotic signaling and mitochondrial dynamics. Controls the dynamic shuffling of syntaxin 17 between ER and mitochondria. Iwasawa et al., 2011; Losón et al., 2013; Nolden et al., 2023; Xian et al., 2019  
INF2 ER Spire1C (mit) INF2-mediated actin polymerization increases MERCs. Promotes increased mitochondrial Ca2+ uptake and IMM constriction. Chakrabarti et al., 2018; Manor et al., 2015  
COPIα Golgi, ER Deficiency decreases MERCs. Regulates mitochondrial distribution, ER morphology, Ca2+ flux. Maddison et al., 2023  
LRRK2 ER MARCH5 (also known as MITOL,
MARCHF5) (mit), MULAN (also
known as MUL1) (mit), parkin (cyt) 
Ablation decreases MERCs (in MEFs).
Controls E3 ubiquitin ligase activity and degradation of MAM proteins through PERK. 
Toyofuku et al., 2020  
DJ-1 (PARK7) ER IP3R3 (mit), GRP75 (mit) Deficiency or mutations reduce MERCs (in M17 neuroblasts, mouse brain). Liu et al., 2019  
Presenilin 2 ER MFN2 (ER, mit) Increases the number of MERCs. Regulates ER-to-mitochondria Ca2+ transfer. Filadi et al., 2016; Zampese et al., 2011  
MIC19 (CHCHD3) ER EMC2 (ER), SLC25A46 (mit) Depletion increases mitochondria–ER distance (in HeLa cells, Cos7 cells). Regulates lipid metabolism. Dong et al., 2024  
Sel1L ER Sigma1R (ER) Depletion increases MERCs. Promotes degradation of Sigma1R. Zhou et al., 2020  
MARCH5 ER MFN2 (ER, mit) Regulates targeting, GTP binding, oligomerization and tethering activity of MFN2 via ubiquitylation of the GTP domain. Sugiura et al., 2013  
Parkin ER, lysosomes MFN2 (ER, mit), Rab7 (lys) Deficiency or mutation decreases MERCs (in human fibroblasts). Regulates tethering through MFN2 ubiquitylation. Regulates amino acid homeostasis. Basso et al., 2018; Peng et al., 2023  
mTOR complex 2 ER IP3R (ER), GRP75 (mit), VDAC1 (mit) Deficiency causes MERC disruption (in MEFs). Phosphorylates IP3R, HK2 and PACS-2 via AKT2. Betz et al., 2013  
TOMM70 ER IP3R (ER), ATG2A (ER) Promotes IP3R recruitment to MAMs,
Ca2+ transfer, ATG2A recruitment to MAMS and phagophore growth. 
Filadi et al., 2018; Tang et al., 2019b  
WFS1 ER Sigma1R (ER), VDAC1 (mit), NCS1 (ER) Mutations decrease MERCs. Regulates Ca2+ transfer and mitophagy. Angebault et al., 2018; Crouzier et al., 2022; Patergnani et al., 2024; Zatyka et al., 2023  
Trichoplein (TCHP) ER MFN2 (ER, mit) Untethering function. Inhibits apoptosis by Ca2+-dependent stimuli. Cerqua et al., 2010  
FATE1 ER Emerin (ER), MIC60 (mit) Untethering function. Reduces Ca2+ transfer. Inhibits apoptosis by Ca2+-dependent stimuli. Doghman-Bouguerra et al., 2016  
TRPV4 ER MFN1 (mit), MFN2 (ER, mit) Expression reduces MERCs (in CHO-K1 cells), increases mitochondrial Ca2+Acharya et al., 2022  
DGAT2 LD, ER FATP1 (also known as SLC27A1) (ER) Under triglyceride (TG) synthesis stimuli, ER–LD contacts are formed close to mitochondria to support synthesis and deposition of TGs into LDs. Stone et al., 2009; Xu et al., 2012  
AMP-activated protein kinase (AMPK) LD AS160 (also known as TBC1D4) (cyt), TBC1D1 (cyt) Involved in contact formation upon starvation. Facilitates transfer of LCFAs to mitochondria. Ouyang et al., 2023  
AS160 LD Rab8A (mit) Deficiency promotes contacts. Ouyang et al., 2023  
ORF6 LD MTX1 (mit), MTX2 (mit), SAMM50 (mit), ATGL (LD) Expression increases contacts (in HeLa cells). Enhances β-oxidation of LCFAs. Yue et al., 2023  
GBA1 Lysosomes TBC1D15 (cyt) Mutants exhibit prolonged contacts. Kim et al., 2021  
STARD3 Lysosomes Depletion reduces contacts. Charman et al., 2010; Hoglinger et al., 2019  
Contact site proteinTethered organelleBinding partners (localization)Effect on contact structure and/or functionReferences
SERCA2 (ATP2A2) ER MFN2 (mit), calnexin (ER) Enhances MERCs (in tumor infiltrating CD8+ T cells). Regulates Ca2+ influx. Gutierrez et al., 2020; Yang et al., 2023  
STIM1 ER TMEM110 (also known as STIMATE) (ER) Increases contacts only upon ER Ca2+ depletion. Garcia Casas et al., 2024  
TESPA1 ER IP3R1 (also known as ITPR1) (ER), GRP75 (mit) Regulates Ca2+ flux. Matsuzaki et al., 2013  
TG2 (TGM2) ER BIP (ER), TOMM70 (mit), GRP75 (mit) Ablation decreases MERC number and alters composition but increases IP3R3 (ITPR3)–GRP75 interaction [in mouse embryonic fibroblasts (MEFs)]. Regulates Ca2+ flux. D'Eletto et al., 2018  
Miro1 and Miro2 ER SAMM50 (mit), MICOS (mit), TRAK1 and TRAK2 (cyt), VPS13D (mit) Double knockout decreases MERCs (in MEFs). Regulates mitochondrial Ca2+ signaling. Recruits VPS13D to mitochondria. Guillen-Samander et al., 2021; Modi et al., 2019  
BCL-2 ER IP3R (ER), CISD2 (ER) Overexpression decreases MERCs and inhibits Ca2+ transfer. Loncke et al., 2025; Namba et al., 2013  
BCL-2L10 ER IRBIT (also known as AHCYL1) (ER), IP3R (ER) Additive inhibition of IP3R with IRBIT. Bonneau et al., 2016  
IRBIT ER IP3R (ER) Upon apoptotic stress, inhibits BCL-2L10,
stimulates MERC formation, regulates
Ca2+ transfer and promotes apoptosis. 
Bonneau et al., 2016  
BOK ER IP3R (ER) Ablation decreases mitochondria–ER proximity and alters MAM composition (in MEFs). Regulates proper localization of MAM proteins, Ca2+ flux and apoptosis control. Carpio et al., 2021  
MCL1 ER BOK (mit) Regulates BOK targeting to MAMs. Increases contact number. Regulates apoptosis. Lucendo et al., 2020  
HK2 ER GRP75 (mit) Loosening of contacts (in HeLa cells). Regulates Ca2+ flux and calpain-dependent cell death. Ciscato et al., 2020  
CCDC127 ER VAPA (ER) Knockdown downregulates MERCs. Stabilizes VAPA. Xia et al., 2023  
PDK4 ER IP3R1 (ER), GRP75 (mit), VDAC1 (mit) Deletion diminishes MERC formation (in skeletal muscle, knockout mice). Increased activity induced by obesity augments MAMs (in C2C12 myoblasts, mouse muscle). Stabilizes the IP3R1–GRP75–VDAC1 complex. Thoudam et al., 2023; Thoudam et al., 2019  
Sigma1R (SIGMAR1) ER Ankyrin (cyt); BIP (ER); IP3R, upon ER Ca2+ depletion or ligand stimulation (ER); IRE1 (also known as ERN1), under ER stress (ER) Stabilizes IP3R. Prolongs Ca2+ release. Mediates stabilization of IRE1 and sensitization to mitochondria-derived ROS. Hayashi and Su, 2007; Joseph et al., 2018; Mori et al., 2013; Wu and Bowen, 2008  
DIAPH1 ER MFN2 (ER, mit) Decreases sarcoplasmic reticulum–mitochondrial distance via RAGE-induced interaction with MFN2 (in cardiomyocytes, endothelial cells, macrophages). Regulates Ca2+ handling, mitophagy and oxidative stress. Yepuri et al., 2023  
PERK ER ESYT1 (ER), Ero1a (ER) Depletion disrupts MERCs (in MEFs). Regulates
Ca2+ signaling, lipid transfer, apoptosis
induction, mitochondrial dynamics and
MERC protein oxidation. 
Bassot et al., 2023; Sassano et al., 2023; Verfaillie et al., 2012  
Ero1a ER IP3R (ER) Promotes oxidation of IP3R. Regulates Ca2+ fluxes. Anelli et al., 2012  
IRE1A ER IP3R (ER) Scaffold function. Regulates distribution of IP3R at MAMs. Promotes enhanced mitochondrial Ca2+ uptake. Carreras-Sureda et al., 2019  
FUNDC1 ER Calnexin (ER), DRP1 (mit), IP3R2 (also known as ITPR2) (ER) Ablation disrupts MAMs (in endothelial cells, neonatal cardiomyocytes). Regulates DRP1 recruitment at MAMs, mitochondrial fission, mitophagy in hypoxia and Ca2+ transfer. Wang et al., 2021a; Wu et al., 2017; Wu et al., 2016  
DRP1 ER MFF, FIS1, MiD49 (also known as MIEF2), MiD51 (also known as MIEF1) (mit); syntaxin 17 (ER); Shrm4 (also known as SHROOM4) (cyt) Promotes ER tubulation and mitochondrial fission. Upon starvation, syntaxin 17 switches its binding from DRP1 to ATG14 and facilitates the formation of autophagosomes. Stimulates formation of MERCs by promoting actin bundling and enhancing the traction anchoring between the ER and mitochondria. Adachi et al., 2020; Arasaki et al., 2015; Duan et al., 2023  
FIS1 ER BAP31, DRP1, syntaxin 17 Regulation of apoptotic signaling and mitochondrial dynamics. Controls the dynamic shuffling of syntaxin 17 between ER and mitochondria. Iwasawa et al., 2011; Losón et al., 2013; Nolden et al., 2023; Xian et al., 2019  
INF2 ER Spire1C (mit) INF2-mediated actin polymerization increases MERCs. Promotes increased mitochondrial Ca2+ uptake and IMM constriction. Chakrabarti et al., 2018; Manor et al., 2015  
COPIα Golgi, ER Deficiency decreases MERCs. Regulates mitochondrial distribution, ER morphology, Ca2+ flux. Maddison et al., 2023  
LRRK2 ER MARCH5 (also known as MITOL,
MARCHF5) (mit), MULAN (also
known as MUL1) (mit), parkin (cyt) 
Ablation decreases MERCs (in MEFs).
Controls E3 ubiquitin ligase activity and degradation of MAM proteins through PERK. 
Toyofuku et al., 2020  
DJ-1 (PARK7) ER IP3R3 (mit), GRP75 (mit) Deficiency or mutations reduce MERCs (in M17 neuroblasts, mouse brain). Liu et al., 2019  
Presenilin 2 ER MFN2 (ER, mit) Increases the number of MERCs. Regulates ER-to-mitochondria Ca2+ transfer. Filadi et al., 2016; Zampese et al., 2011  
MIC19 (CHCHD3) ER EMC2 (ER), SLC25A46 (mit) Depletion increases mitochondria–ER distance (in HeLa cells, Cos7 cells). Regulates lipid metabolism. Dong et al., 2024  
Sel1L ER Sigma1R (ER) Depletion increases MERCs. Promotes degradation of Sigma1R. Zhou et al., 2020  
MARCH5 ER MFN2 (ER, mit) Regulates targeting, GTP binding, oligomerization and tethering activity of MFN2 via ubiquitylation of the GTP domain. Sugiura et al., 2013  
Parkin ER, lysosomes MFN2 (ER, mit), Rab7 (lys) Deficiency or mutation decreases MERCs (in human fibroblasts). Regulates tethering through MFN2 ubiquitylation. Regulates amino acid homeostasis. Basso et al., 2018; Peng et al., 2023  
mTOR complex 2 ER IP3R (ER), GRP75 (mit), VDAC1 (mit) Deficiency causes MERC disruption (in MEFs). Phosphorylates IP3R, HK2 and PACS-2 via AKT2. Betz et al., 2013  
TOMM70 ER IP3R (ER), ATG2A (ER) Promotes IP3R recruitment to MAMs,
Ca2+ transfer, ATG2A recruitment to MAMS and phagophore growth. 
Filadi et al., 2018; Tang et al., 2019b  
WFS1 ER Sigma1R (ER), VDAC1 (mit), NCS1 (ER) Mutations decrease MERCs. Regulates Ca2+ transfer and mitophagy. Angebault et al., 2018; Crouzier et al., 2022; Patergnani et al., 2024; Zatyka et al., 2023  
Trichoplein (TCHP) ER MFN2 (ER, mit) Untethering function. Inhibits apoptosis by Ca2+-dependent stimuli. Cerqua et al., 2010  
FATE1 ER Emerin (ER), MIC60 (mit) Untethering function. Reduces Ca2+ transfer. Inhibits apoptosis by Ca2+-dependent stimuli. Doghman-Bouguerra et al., 2016  
TRPV4 ER MFN1 (mit), MFN2 (ER, mit) Expression reduces MERCs (in CHO-K1 cells), increases mitochondrial Ca2+Acharya et al., 2022  
DGAT2 LD, ER FATP1 (also known as SLC27A1) (ER) Under triglyceride (TG) synthesis stimuli, ER–LD contacts are formed close to mitochondria to support synthesis and deposition of TGs into LDs. Stone et al., 2009; Xu et al., 2012  
AMP-activated protein kinase (AMPK) LD AS160 (also known as TBC1D4) (cyt), TBC1D1 (cyt) Involved in contact formation upon starvation. Facilitates transfer of LCFAs to mitochondria. Ouyang et al., 2023  
AS160 LD Rab8A (mit) Deficiency promotes contacts. Ouyang et al., 2023  
ORF6 LD MTX1 (mit), MTX2 (mit), SAMM50 (mit), ATGL (LD) Expression increases contacts (in HeLa cells). Enhances β-oxidation of LCFAs. Yue et al., 2023  
GBA1 Lysosomes TBC1D15 (cyt) Mutants exhibit prolonged contacts. Kim et al., 2021  
STARD3 Lysosomes Depletion reduces contacts. Charman et al., 2010; Hoglinger et al., 2019  

Cyt, cytosol; lys, lysosome; mit, mitochondrion.

In this Cell Science at a Glance article and the accompanying poster, we summarize known tethers found between mammalian mitochondria and other membranous organelles, their regulators and their main roles in cell physiology.

Mitochondria–ER contacts (MERCs), perhaps the best characterized mitochondrial MCSs, are crucial hubs for lipid trafficking and Ca2+ flux in physiology and disease (de Ridder et al., 2023; Loncke et al., 2021; Sassano et al., 2022; Vance, 2020), and they also play roles in aspects of protein homeostasis and quality control, stress responses, control of cell death, and organelle dynamics (see poster).

PACS-2

The sorting protein PACS-2 was the first molecular regulator of MERCs to be discovered (Simmen et al., 2005). PACS-2 participates in Ca2+ transfer, which might depend on PACS-2 protein-sorting function: the Ca2+ regulatory protein calnexin (CNX) as well as polycystin-2, which interacts with the ER Ca2+-release channel inositol 1,4,5-trisphosphate receptor (IP3R; herein referring collectively to ITPR1, ITPR2 and ITPR3) and mitofusin 2 (MFN2), are both cargos of PACS-2, which controls their distribution to MAMs (Kuo et al., 2019; Myhill et al., 2008; Sammels et al., 2010). In addition, PACS-2 regulates the levels of some lipid-synthesizing enzymes, such as PSS1 (also known as PTDSS1) and FACL4 (also known as ACSL4), at MAMs through a still unknown mechanism (Simmen et al., 2005). PACS-2 silencing results in cleavage of the integral ER membrane protein BAP31 (also known as BCAP31) to p20BAP31, followed by mitochondrial fragmentation and uncoupling from the ER (Simmen et al., 2005). BAP31 has more recently been shown to form a tethering complex with the mitochondrial fission protein FIS1 that acts as a platform for procaspase 8 activation at MAMs and propagates the apoptotic signal from mitochondria to ER (Iwasawa et al., 2011). BAP31 also plays a role in targeting of mitochondrial precursor proteins through an ER stress-sensitive interaction with the mitochondrial import receptor subunit TOMM40 at MAMs. This complex favors translocation of NADH dehydrogenase enzymes NDUFS4 and NDUFB11 to mitochondria, thereby regulating complex I activity (Namba, 2019). Thus, the role of PACS-2 in controlling the extent of MERCs appears indirect (that is, not mediated by an interaction in trans with another protein on the OMM).

IP3R, VDAC1 and GRP75

In 2006, a tripartite complex formed by the OMM voltage-dependent channel VDAC1 with IP3R, stabilized by the OMM-associated fraction of the chaperone GRP75 (also known as HSPA9), was described (Szabadkai et al., 2006) (see poster). All IP3R subtypes localize at MERCs (Bartok et al., 2019) and are tightly controlled by many MERC-residing proteins (Table 1). IP3Rs are central in Ca2+ transfer between compartments but also play a Ca2+-independent structural role in forming MERCs (Katona et al., 2022). Opening of IP3R on the ER leads to efflux of Ca2+, which is then taken up into the mitochondrial matrix via VDAC1 in the OMM and the mitochondrial Ca2+ uniporter (MCU) in the inner mitochondrial membrane (IMM) (de Stefani et al., 2011; Rizzuto et al., 1998). These proteins, strategically placed at MERCs, provide the spatial unit that makes mitochondrial Ca2+ uptake possible. Indeed, the Ca2+ affinity of the MCU is more than an order of magnitude higher than bulk cytosolic Ca2+ concentrations. MERCs thus create a separate microdomain of high Ca2+ concentration at levels permissive for uptake by mitochondria (Csordas et al., 2010; Giacomello et al., 2010). Despite the importance of this complex, as with PACS-2, it also has no direct effect on the proximity of the two tethered organelles.

Mitofusin 2

MFN2 was the first bona fide structural mitochondria–ER tether identified in mammalian cells. A fraction of MFN2, which is a dynamin-related protein that promotes mitochondrial fusion, localizes in MAMs and engages in homotypic or heterotypic interactions with other MFN2 molecules or mitofusin 1 (MFN1) on the OMM (de Brito and Scorrano, 2008). In addition, deletion of MFN2 increases the distance between ER and mitochondria and diminishes agonist-stimulated ER-to-mitochondria Ca2+ transfer. Whereas some studies have challenged the role of MFN2 as a tether (Cosson et al., 2012; Filadi et al., 2015; Leal et al., 2016), many others support this function (Chen et al., 2012; Göbel et al., 2020; Li et al., 2015; Liao et al., 2024; Naon et al., 2016; Schneeberger et al., 2013; Sebastian et al., 2012), highlighting the complexity of these interorganellar interfaces. MFN2-mediated tethering is regulated by a variety of post-translational modifications and protein interactions, further supporting its essential role in maintaining MERCs (Table 1). However, how such an important cellular function could be accomplished by an ectopically localized fraction of primarily mitochondrially localized MFN2 remained unclear until the recent discovery of purely extramitochondrial splice variants of the MFN2 gene, dubbed ERMIN2 and ERMIT2 (Naon et al., 2023) (see poster). ERMIN2 retains the part of the MFN2 GTPase domain essential for promoting mitochondrial fusion and can restore normal ER morphology in MFN2-deficient cells, whereas ERMIT2, which lacks the GTPase domain but retains the CC2 domain essential for interactions with the CC1 or CC2 domains of mitochondrial mitofusins, tethers the ER to mitochondria (Naon et al., 2023).

MERC tethers and ER lipid homeostasis

Several other physical tethers at MERCs have been identified and characterized. The interaction between VAPB on the ER and PTPIP51 (also known as RMDN3) on the OMM establishes a tethering complex that regulates Ca2+ homeostasis (de Vos et al., 2012). VAPB and PTPIP51 are often found at interorganellar interfaces at synapses, and their depletion reduces synaptic activity, a pathological feature in several neurodegenerative diseases (Gomez-Suaga et al., 2019). PTPIP51 phosphorylation and subsequent binding to VAPB is increased by mitochondrial reactive oxygen species (ROS), and PTPIP51 performs an antioxidant function by removing lipid radicals from mitochondria via MERCs through the lipid radical-transfer activity of its tetratricopeptide repeat (TPR) domain (Shiiba et al., 2025). Recently, the lipid transfer protein (LTP) VPS13D has been shown to bind to VAPA and VAPB and tether the ER to mitochondria in a manner dependent on mitochondrial Rho GTPase (Miro; herein referring to Miro1 and Miro2, also known as RHOT1 and RHOT2, respectively) (Guillen-Samander et al., 2021). PTPIP51 also interacts with the LTPs ORP5 (OSBPL5) and ORP8 (OSBPL8) at MAMs, and loss of these proteins leads to mitochondrial defects (Galmes et al., 2016). ORP5 and ORP8 were initially described at ER–plasma membrane (PM) contacts, where they transfer phosphatidylserine (PS) from the cortical ER to the PM in counter-exchange for phosphatidylinositol-4-phosphate (PI4P) from the PM (Chung et al., 2015). In MAMs, ORP5 and ORP8 have been shown to mediate the transport of PS from the ER to mitochondria by cooperating with two protein complexes that bridge the IMM and OMM, the mitochondrial intermembrane space bridging (MIB) complex and the mitochondrial contact sites and cristae junction organizing system (MICOS) complex (Monteiro-Cardoso et al., 2022), and to control lipid droplet (LD) biogenesis by recruiting seipin at MAMs (Guyard et al., 2022). Because the TPR domain of PTPIP51 can transfer phosphatidic acid (PA) (Yeo et al., 2021), its interaction with ORP5 and ORP8 might also mediate PS trafficking.

PERK (also known as EIF2AK3), an effector of the unfolded protein response (UPR), recruits and scaffolds the ER protein ESYT1 at MERCs (Sassano et al., 2023) to regulate phospholipid (PL) transfer, and disruption of this interaction or the lipid transfer function of ESYT1 causes mitochondrial respiration and lipid transfer defects. Depletion of PERK but not ESYT1 has been shown to reduce the number of MERCs per cell. ESYT1 forms a tethering complex with the OMM protein SYNJ2BP (Janer et al., 2024). Depletion of either protein has been shown to reduce the number and length of MERCs and impair mitochondrial Ca2+ uptake and lipid homeostasis, whereas overexpression of SYNJ2BP promotes MERC formation. SYNJ2BP also interacts with the ribosome-binding protein RRBP1, forming a mitochondria–rough ER contact of ∼45 nm (Hung et al., 2017); however, whether this represents a bona fide tethering complex remains to be ascertained.

MERC tethers in protein homeostasis and ER stress

Recently, PERK has also been found to interact with ATAD3A (Brar et al., 2024), an AAA+ ATPase that spans the intermembrane space (IMS), with its C terminus in the matrix and N terminus anchored in the OMM (Gilquin et al., 2010). This interaction tethers the ER to mitochondria during ER stress and protects key mitochondrial proteins from PERK-mediated translational repression. In breast cancer cells, a complex containing ATAD3A, WASF3 and BIP (HSPA5) stabilizes WASF3 in the OMM and creates a bridge to the ER (Teng et al., 2016). ATAD3A supports several MERC-related functions, such as steroid and lipid synthesis, mitochondrial DNA maintenance, and regulation of mitochondrial morphology (Gerhold et al., 2015; Gilquin et al., 2010; He et al., 2007; Issop et al., 2015), as well as regulation of mitochondrial ribosome assembly and stability, and cristae morphology (Rigoni et al., 2025). It is therefore possible that all these functions are coordinated by ATAD3A-mediated tethering at MERCs.

Another UPR and ER stress regulator localized at MAMs is PIGBOS (also known as PIGBOS1), an OMM microprotein (a small peptide or protein translated from a small open reading frame). Interaction of PIGBOS with the ER protein CLCC1 at MAMs is necessary for the function of PIGBOS in the regulation of the UPR and ER stress-induced apoptosis (Chu et al., 2019). However, depletion or overexpression of PIGBOS has no effect on MERC formation.

Other tethers at MERCs

The ER transmembrane protein PDZD8 has also been identified as a MERC tether (Hirabayashi et al., 2017). PDZD8 contains a synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain that is functionally orthologous to yeast Mmm1, a subunit of the ER–mitochondria encounter structure (ERMES) that tethers mitochondria to ER in yeast (Kornmann et al., 2009). Its long-sought tethering partner on the OMM has recently been found to be FKBP8 (Nakamura et al., 2025). PDZD8 influences mitochondrial morphology in a FKBP8-dependent manner, suggesting that this tethering complex regulates mammalian mitochondrial shape. In neurons, PDZD8 is required for Ca2+ uptake by mitochondria after synaptic-induced Ca2+ release from the ER (Hirabayashi et al., 2017). Another potential MERC tether is REEP1, which contains a receptor expression-enhancing protein (REEP) homology domain, shown to insert into membranes as a hairpin and modulate membrane curvature. REEP1 also contains subdomains for mitochondrial and ER localization and is found in MAMs, where it facilitates MERC formation (Lim et al., 2015). Lastly, many MERC tethering proteins also participate in formation of tripartite contacts between mitochondria, ER and other organelles (Box 1; see poster).

Mitochondria–ER–autophagosome contacts

MERCs play a pivotal role in autophagophore biogenesis (Hamasaki et al., 2013). The mitochondrial import receptors TOMM40 and TOMM70 recruit ATG2A at MERCs, which then recruits ATG9A, promoting phagophore growth (Tang et al., 2019a,b) by lipid transfer (Valverde et al., 2019; Wang et al., 2024). Many MERC tethers regulate autophagosome formation; for example, PACS-2 regulates syntaxin 17-dependent recruitment of ATG14 at MAMs (Hamasaki et al., 2013) and mitophagosome formation at MERCs in human vascular smooth muscle cells (Moulis et al., 2019), and VAPB and PTPIP51 regulate autophagy through their role in mitochondrial Ca2+ uptake (Gomez-Suaga et al., 2017) and by enhancing and stabilizing local recruitment of multiple autophagy-related proteins, such as the ULK1 signaling complex (Zhao et al., 2018). In Drosophila, the OMM protein mitoguardin 2 (MIGA2) interacts with Atg14 and UV radiation resistance-associated gene (Uvrag) to regulate syntaxin 17 stability and phosphoinositide 3-kinase activity during the formation of omegasomes, which are omega-shaped membrane structures formed where phagophores initially assemble at MERCs (Xu et al., 2022).

Mitochondria–ER–endolysosome contacts

Both mitochondria and lysosomes form contacts with the ER that are fundamental for Ca2+ transfer, PL and cholesterol trafficking, and mitochondrial division. The ER recruits lysosomes to the site of mitochondrial division to form a tripartite contact mediated by Rab7, VAPA, VAPB and ORP1L (also known as OSBPL1A), a lysosomal LTP (Boutry and Kim, 2021). The lipid transfer domain of ORP1L is suggested to provide PI4P to the mitochondrial division site. Recently, the trans-Golgi network (TGN) has been added to this equation. The small GTPase Arf1 and its effector PI4KIIIβ (PI4KB) have been found on interfaces between mitochondria, ER and the Golgi, enabling the accumulation of PI4P puncta on TGN vesicles, which drives late steps of mitochondrial division (Nagashima et al., 2020).

PDZD8 also mediates the formation of both ER–endolysosome and ER–mitochondria contacts, bringing together the three organelles (Elbaz-Alon et al., 2020). Through distinct domains, PDZD8 interacts with GTP-bound Rab7 on endosomes and the ER protein protrudin during a stage of endosomal maturation marked by recruitment of the Rab7 effector WDR91, which controls phosphoinositide conversion (Casanova and Winckler, 2017) to define the specific identity of the endosomal membrane and regulate signaling pathways (Posor et al., 2022). However, whether this tripartite contact also involves FKBP8 on mitochondria or another mitochondrial protein is not known. In neurons, the protrudin–PDZD8 interaction promotes endosome maturation via lipid extraction at ER–lysosome contacts, maintaining neuronal integrity (Shirane et al., 2020).

Another tripartite contact is formed by members of the VPS13 family of human LTPs. The ER is tethered to mitochondria and late endosomes or lysosomes through VPS13A and VPS13C, respectively (Kumar et al., 2018). This tripartite contact potentially controls lipid trafficking, as the N-terminal heads of VPS13 proteins form a lipid transport module that can harbor glycerolipids and transfer them between bilayers.

Mitochondria–ER–lipid droplet contacts

In differentiating white adipocytes, the FFAT motif of MIGA2 on the OMM binds to VAPA or VAPB on the ER membrane, tethering the two organelles, while an amphipathic segment in the MIGA2 C terminus binds to the surface of LDs. It has been suggested that this tripartite contact between mitochondria, ER and LDs regulates the de novo synthesis of triacylglycerol from non-lipid precursors (Freyre et al., 2019). A recent structural study has demonstrated that MIGA2 specifically transfers PS between two membranes (Kim et al., 2022).

Mitochondria and peroxisomes are functionally interconnected, co-participating in α- and β-oxidation, bile acid synthesis, steroid biosynthesis, ROS metabolism, glyoxylate detoxification, and anti-viral signaling and response (Wanders et al., 2023). Like mitochondria, peroxisomes are morphologically dynamic organelles, and both organelles share core fission machinery: FIS1, mitochondrial fission factor (MFF), ganglioside-induced differentiation-associated protein 1 (GDAP1) and dynamin-related protein 1 (DRP1, also known as DNM1L) (Subramani et al., 2023). The first mitochondria–peroxisome tethering complex to be identified was found in Leydig cells and includes the acyl-CoA-binding protein ACBD2/ECI2 isoform A (encoded by ECI2), which localizes in both peroxisomes and mitochondria via competitive binding between PEX5 on peroxisomes and TOMM20 on mitochondria, bringing the two organelles close (see poster) (Fan et al., 2016). Ectopic expression of ACBD2/ECI2 isoform A in MA-10 cells, derived from a mouse Leydig cell tumor, increases steroid biosynthesis, suggesting that mitochondria source the cholesterol required for this process via peroxisome contacts.

PEX11β (also known as PEX11B), a key regulator of peroxisomal membrane dynamics and division (Koch et al., 2010; Schrader et al., 2022), has also been identified as a potential mitochondria–peroxisome tether (Kustatscher et al., 2019). PEX11β is co-regulated with subunits of the mitochondrial ATP synthase and other components of the electron transport chain (Kustatscher et al., 2019). Its expression induces the formation of peroxisomal membrane protrusions, facilitating interactions with mitochondria. However, it remains unknown whether PEX11β tethers the membranes of the two organelles or what the identity of its partners on mitochondria might be.

Mitofusins also contribute to co-clustering of mitochondria and peroxisomes as a potential tether between these organelles (Huo et al., 2022). MFN2 is enriched at mitochondria–peroxisome contacts, and upregulation of MFN2 via leflunomide treatment stimulates contact formation, whereas the expression of a dominant-negative MFN2 mutant inhibits it. In yeast, modulation of levels of the mitofusin ortholog Fzo1 by the ubiquitin–proteasome system and the desaturation status of fatty acids (FAs) regulates the formation of homotypic Fzo1-mediated mitochondria–peroxisome contacts to facilitate the transfer of peroxisomal citrate to mitochondria (Alsayyah et al., 2024).

Mitochondria and endolysosomes also exhibit crosstalk to regulate key cellular processes, including autophagy, nutrient and energy homeostasis, stress and immune responses, proliferation, apoptosis, cell death signaling, and iron and heme metabolism (see poster), as evidenced by the impact of mitochondrial defects on lysosomal biogenesis and function, and vice versa (Deus et al., 2020). The physical contacts between mitochondria and lysosomes (mitochondria–lysosome contacts, MLCs) in mammals display a distance of ∼10 nm (Wong et al., 2018) and vary in duration (Han et al., 2017). Deregulation of MLCs is involved in the pathogenesis of several diseases, including Parkinson's disease, Charcot–Marie–Tooth (CMT) disease and lysosomal storage disorders such as mucolipidosis type IV (Cantarero et al., 2021; Kim et al., 2021; Peng et al., 2020; Rizzollo and Agostinis, 2025; Wong et al., 2019; Xie et al., 2024).

Rab7 at contacts between mitochondria and late endolysosomes

The small GTPase Rab7 (herein referring to both Rab7A and Rab7B) promotes MLC formation in its lysosomal GTP-bound form, and tethering to mitochondria is probably mediated through Rab7 effector proteins (Wong et al., 2018). Untethering is mediated by Rab7 GTP hydrolysis stimulated by TBC1D15, a Rab7 GTP-hydrolysis-activating protein (GAP) that is recruited to mitochondria by FIS1 (Onoue et al., 2013). This mitochondria–lysosome tethering thus regulates mitochondrial fission (Wong et al., 2018). Although TBC1D15 has no known role in contact formation, reducing its activity has proven beneficial in disease models (Kim et al., 2021; Sun et al., 2022; Yu et al., 2020). Active Rab7 interacts with the NPC1 cholesterol transporter and stimulates lysosomal cholesterol export, a process regulated by the trimeric Mon1-Ccz1-C18orf8 (MCC) complex, which acts as a Rab7 guanine-nucleotide-exchange factor (GEF) (van den Boomen et al., 2020). Downstream of mTOR complex 1 (mTORC1) signaling, Rab7A controls cholesterol trafficking from lysosomes to mitochondria by regulating the interaction between translocator protein (TSPO) on the OMM and NPC1 on lysosomes (Lin et al., 2023). Interestingly, in the absence of NPC1, lysosomes form extensive contacts with mitochondria that are dependent on the LTP STARD3 (Hoglinger et al., 2019). In hepatocellular carcinoma, Rab7 interacts with a phosphorylated form of DRP1 (p-DRP1S616) at MLCs, triggers PINK1–parkin (PRKN)-dependent mitophagy (the selective degradation of mitochondria via autophagy) and promotes cell survival. The PP2A phosphatase subunit B56γ (also known as PPP2R5C) negatively regulates MLC formation via dephosphorylation of p-DRP1S616, leading to apoptosis and sensitization of cells to chemotherapy (Che et al., 2022). Interestingly, the mouse DRP1ABCD isoform, which is enriched in brain and is involved in mitochondrial and peroxisomal division, localizes to the interface between mitochondria and lysosomes or late endosomes without participating in contact formation (Itoh et al., 2018). Rab7A is also found on late endosomes that interact with RNA granules, which often dock at mitochondria in axons, where they control the synthesis of pro-survival proteins (Cioni et al., 2019). These RNA-bearing late endosomes also associate with ribosomes, and disruption of their function affects the local translation efficiency of mRNAs essential for mitochondrial function, but the exact role of these mitochondria–endosome contacts is not known.

Mitochondria–lysosome tethers in Ca2+ and iron homeostasis

MLCs also modulate intracellular Ca2+ fluxes via the direct transfer of lysosomal Ca2+ to mitochondria, mediated by the interaction of the nonselective cation channel TRPML1 (also known as MCOLN1) on lysosomes with VDAC1 on the OMM (Peng et al., 2020). However, whether TRPML1 and VDAC1 act as a tether is unclear because expression of a dominant-negative nonconducting TRPML1 pore mutant increases the incidence of stable MLCs (Peng et al., 2020).

GDAP1, an atypical glutathione S-transferase (GST) located on the OMM and at MAMs, can interact with the lysosome-associated membrane protein LAMP1, forming a redox-sensitive tether between mitochondria and lysosomes in neurons (Cantarero et al., 2021). Depletion of GDAP1 reduces MLCs and glutathione levels, resulting in lysosomal and mitochondrial network abnormalities. Pathogenic variants of GDAP1 that cause CMT disease display different effects on MLCs as well as on cellular and mitochondrial Ca2+ levels, suggesting a potential role for MLCs in the observed differences in severity between dominant and recessive forms (Cantarero et al., 2023).

Lastly, in erythroid cells, MLCs are assembled by MFN2 to facilitate transferrin receptor 2 (TfR2)-dependent transferrin (Tf) delivery to lysosomes. MFN2 knockdown reduces MLC numbers, total heme content and erythroid differentiation (Khalil et al., 2017).

Melanosomes are organelles responsible for the synthesis, storage and transport of melanin. MFN2 tethers mitochondria to melanosomes through fibrillar bridges (Daniele et al., 2014) (see poster), and its knockdown reduces both formation of mitochondria–melanosome contacts and activation of melanogenesis. Close mitochondria–melanosome contact might facilitate ATP supply for melanosome biogenesis. However, a recent study has demonstrated an opposing role for MFN2 as a negative regulator of melanogenesis (Tanwar et al., 2022).

Mitochondrial–lipid droplet contacts (MLDCs) form to channel FAs between the two organelles or to channel ATP from mitochondria to LDs to support lipid synthesis. On LDs, perilipins play a crucial role in establishing MLDCs (see poster). The first tether described to link LDs to mitochondria and regulate oxidative LD hydrolysis and FA flux was perilipin 5 (Wang et al., 2011a), the C terminus of which is necessary and sufficient to mediate MLDCs. In myoblasts, perilipin 5 interacts with the acyl-CoA synthetase FATP4 (also known as SLC27A4) on the OMM, and this interaction is specifically required for FA channeling (Miner et al., 2023). Upon starvation in skeletal muscle, perilipin 5 interacts with GTP-bound, active Rab8A and recruits adipose triglyceride lipase (ATGL, also known as PNPLA2) to promote long-chain FA (LCFA) transfer into mitochondria for β-oxidation (Ouyang et al., 2023). Perilipin 5 and another member of the perilipin family, perilipin 1, interact with MFN2 in human bone osteosarcoma epithelial cells (U2OS cells; Miner et al., 2023) and adipose tissue, forming contacts that assemble in response to adrenergic stimulation and couple triglyceride hydrolysis to FA oxidation (Boutant et al., 2017). In hepatocytes exposed to aflatoxin B1, perilipin 2 forms a tethering complex with mitochondria-translocated p53 (TP53) that inhibits lysosome-associated lipophagy, leading to lipid accumulation and lipotoxicity (Che et al., 2023). Removal of perilipins via chaperone-mediated autophagy is indeed necessary for initiation of lipolysis by lipases or lipophagy (Kaushik and Cuervo, 2015).

The synaptosomal-associated protein receptor (SNARE) protein SNAP23, found on LDs, modulates both MLDC formation and β-oxidation in NIH3T3 fibroblasts. However, these two effects appear not to be linked, and the molecular mechanism by which SNAP23 functions is still unknown (Jagerstrom et al., 2009). During glucose deprivation, when FA oxidization is stimulated, SNAP23 and VAMP4 associate with ACSL1 on mitochondria, tethering LDs to the OMM (Young et al., 2018). ACSL1 has been shown to be recruited to mitochondria by TBK1, which operates as a molecular rheostat to control hepatic FA oxidation (Huh et al., 2020). However, SNAP23 tethering is not essential for the flow of FAs from LDs to mitochondria. FA transfer from LDs also occurs via membrane remodeling facilitated through association between VPS13D and the endosomal sorting complex required for transport (ESCRT) protein TSG101 at MLDCs: the N-terminal domain of VPS13D targets mitochondria, whereas the C terminus targets LDs and the Vps13 adaptor-binding (VAB) domain interacts with TSG101 (Wang et al., 2021b). Suppression of VPS13D, but not TSG101, significantly reduces the incidence of MLDCs (Wang et al., 2021b).

Physical tethering between mitochondria and the nucleus participates in regulation of cholesterol trafficking, protein distribution and transcriptional activity (see poster). During mitochondrial retrograde response (MRR) signaling, mitochondria–nucleus tethering occurs through the interaction of TSPO, which recruits ACBD3 to mitochondria, and protein kinase A (PKA), which also interacts with the A-kinase anchoring protein AKAP95 (also known as AKAP8) on the nuclear membrane (Desai et al., 2020). In breast cancer cells, formation of these nucleus-associated membranes facilitates trafficking of cholesterol to the nucleus, sustaining a pro-survival response by blocking NF-κB deacetylation. In response to proliferative stimuli, MFN2 also tethers mitochondria to the nucleus in a noncanonical pathway for importing the IMM pyruvate dehydrogenase complex (PDC) into the nucleus. Nuclear PDC retains its enzymatic activity, interacts with the nuclear lamina matrix protein lamin A and possibly participates in protein acetylation at nucleoplasmic hubs (Zervopoulos et al., 2022).

In the past two decades, our understanding of organellar communication and functional coordination has significantly evolved. Organelles, once considered isolated units, are now recognized as components of a physically and functionally interconnected dynamic network. However, despite considerable advances, several challenges remain. Foremost is the development of efficient, user-friendly techniques and tools for visualizing contact sites and identifying the molecular tethers that stabilize them. Following the consensus on the ontology of tethers reached in 2019 (Scorrano et al., 2019), the field must also reach agreement on methodologies and data interpretation.

As additional mitochondrial contacts with various organelles are discovered, the gaps in our knowledge regarding the (co-)regulation of tethering machineries become more apparent. Recent studies have revised our notion of organellar tethers from stable, static bridges to dynamic, orchestrated connections applied by many functional interactions in response to specific stimuli. Stimulus-triggered rearrangements in mitochondrial contacts might involve single or multiple tethers, last for differing durations, and lead to distinct outcomes depending on the duration or intensity of stimuli. This structural and temporal flexibility ensures that MCSs can adapt to changing needs without compromising cell function. For example, a transient increase in MERCs facilitates Ca2+ transfer from the ER to mitochondria, stimulating metabolic enzymes and ATP production, whereas prolonged tethering might lead to Ca2+ overload and apoptosis. Similarly, transient ER stress increases MERCs and leads to enhanced ATP production (Bravo et al., 2011), whereas chronic UPR activation has the opposite effect (Wang et al., 2011b).

The plasticity of MCSs in response to nutrient availability is particularly well documented (Benador et al., 2018; Boutant et al., 2017; Honscher et al., 2014; Sood et al., 2014; Theurey et al., 2016; Young et al., 2018) and is typically periodic – MCSs adjust their number, extent and structure to meet metabolic demands before returning to a steady state. These shifts occur on the order of hours (Sood et al., 2014), in contrast to Ca2+-related remodeling, which can occur in seconds (Yi et al., 2004). High-speed molecular tracking of VAPB has recently demonstrated the dynamic nature of mitochondrial contacts by revealing rapid diffusion of VAPB molecules in and out of a long-lasting contact site that quickly remodels in response to metabolic cues (Obara et al., 2024). In addition, LTPs such as ESYT1, ORP5 and ORP8 form bridges by binding to specific lipids in organelle membranes (Galmes et al., 2016; Saheki and De Camilli, 2017) or by tethering different organelles to allow them to utilize specific fuels, as in the case of VPS13D (Wang et al., 2021b), suggesting that precise tethering mechanisms function to meet metabolic demands. Mitochondrial contacts are also remodeled in response to physiological processes such as mitosis (Yu et al., 2024; Zhao et al., 2024), and these rearrangements are transient, lasting only until the completion of the process. However, key questions regarding MCS dynamics remain, including how the proteins localized in these specialized subcompartments coordinate to maintain or dissolve contacts and how universal tethers, such as MFN2, are regulated.

Finally, perturbations in mitochondrial contacts and their tethering protein machinery have been linked to multiple diseases (Cisneros et al., 2022; Fan and Tan, 2024; Makio and Simmen, 2024; Morcillo et al., 2024; Rizzollo and Agostinis, 2025; Wilson and Metzakopian, 2021). Clarifying the molecular mechanisms and identifying the specific players involved in these pathological conditions is crucial for developing effective treatments. The challenge remains to specifically target these perturbations without disrupting the processes that occur at contact sites.

We thank the members of the Scorrano lab for helpful discussions.

Funding

Our work in this area is supported by Ministry for Universities and Research, Italian Fund for Science Advanced Grant FIS00001005 (CUP C53C23000420001) to L.S. A.D. is the recipient of a Fondazione Umberto Veronesi postdoctoral fellowship. Open Access funding provided by the Ministry for Universities and Research Italian Fund for Science Advanced Grant FIS00001005. Deposited in PMC for immediate release.

High-resolution poster and poster panels

A high-resolution version of the poster and individual poster panels are available for downloading at https://journals.biologists.com/jcs/article-lookup/doi/10.1242/jcs.263895#supplementary-data.

Special Issue

This article is part of the Special Issue ‘Cell Biology of Mitochondria’, guest edited by Ana J. Garcia-Saez and Heidi McBride. See related articles at https://journals.biologists.com/jcs/issue/138/9.

Acharya
,
T. K.
,
Kumar
,
A.
,
Kumar
,
S.
and
Goswami
,
C.
(
2022
).
TRPV4 interacts with MFN2 and facilitates endoplasmic reticulum-mitochondrial contact points for Ca(2+)-buffering
.
Life Sci.
310
,
121112
.
Adachi
,
Y.
,
Kato
,
T.
,
Yamada
,
T.
,
Murata
,
D.
,
Arai
,
K.
,
Stahelin
,
R. V.
,
Chan
,
D. C.
,
Iijima
,
M.
and
Sesaki
,
H.
(
2020
).
Drp1 tubulates the ER in a GTPase-independent manner
.
Mol. Cell
80
,
621
-
632.e6
.
Alsayyah
,
C.
,
Singh
,
M. K.
,
Morcillo-Parra
,
M. A.
,
Cavellini
,
L.
,
Shai
,
N.
,
Schmitt
,
C.
,
Schuldiner
,
M.
,
Zalckvar
,
E.
,
Mallet
,
A.
,
Belgareh-Touzé
,
N.
et al.
(
2024
).
Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion
.
PLoS Biol.
22
,
e3002602
.
Anelli
,
T.
,
Bergamelli
,
L.
,
Margittai
,
E.
,
Rimessi
,
A.
,
Fagioli
,
C.
,
Malgaroli
,
A.
,
Pinton
,
P.
,
Ripamonti
,
M.
,
Rizzuto
,
R.
and
Sitia
,
R.
(
2012
).
Ero1alpha regulates Ca(2+) fluxes at the endoplasmic reticulum-mitochondria interface (MAM)
.
Antioxid Redox Signal.
16
,
1077
-
1087
.
Angebault
,
C.
,
Fauconnier
,
J.
,
Patergnani
,
S.
,
Rieusset
,
J.
,
Danese
,
A.
,
Affortit
,
C. A.
,
Jagodzinska
,
J.
,
Megy
,
C.
,
Quiles
,
M.
,
Cazevieille
,
C.
et al.
(
2018
).
ER-mitochondria cross-talk is regulated by the Ca(2+) sensor NCS1 and is impaired in Wolfram syndrome
.
Sci. Signal.
11
,
eaaq1380
.
Arasaki
,
K.
,
Shimizu
,
H.
,
Mogari
,
H.
,
Nishida
,
N.
,
Hirota
,
N.
,
Furuno
,
A.
,
Kudo
,
Y.
,
Baba
,
M.
,
Baba
,
N.
,
Cheng
,
J.
et al.
(
2015
).
A role for the ancient SNARE syntaxin 17 in regulating mitochondrial division
.
Dev. Cell
32
,
304
-
317
.
Bartok
,
A.
,
Weaver
,
D.
,
Golenar
,
T.
,
Nichtova
,
Z.
,
Katona
,
M.
,
Bánsághi
,
S.
,
Alzayady
,
K. J.
,
Thomas
,
V. K.
,
Ando
,
H.
,
Mikoshiba
,
K.
et al.
(
2019
).
IP(3) receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer
.
Nat. Commun.
10
,
3726
.
Basso
,
V.
,
Marchesan
,
E.
,
Peggion
,
C.
,
Chakraborty
,
J.
,
Von Stockum
,
S.
,
Giacomello
,
M.
,
Ottolini
,
D.
,
Debattisti
,
V.
,
Caicci
,
F.
,
Tasca
,
E.
et al.
(
2018
).
Regulation of ER-mitochondria contacts by Parkin via Mfn2
.
Pharmacol. Res.
138
,
43
-
56
.
Bassot
,
A.
,
Chen
,
J.
,
Takahashi-Yamashiro
,
K.
,
Yap
,
M. C.
,
Gibhardt
,
C. S.
,
Le
,
G. N. T.
,
Hario
,
S.
,
Nasu
,
Y.
,
Moore
,
J.
,
Gutierrez
,
T.
et al.
(
2023
).
The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria
.
Cell Rep.
42
,
111899
.
Benador
,
I. Y.
,
Veliova
,
M.
,
Mahdaviani
,
K.
,
Petcherski
,
A.
,
Wikstrom
,
J. D.
,
Assali
,
E. A.
,
Acin-Perez
,
R.
,
Shum
,
M.
,
Oliveira
,
M. F.
,
Cinti
,
S.
et al.
(
2018
).
Mitochondria bound to lipid droplets have unique bioenergetics, composition, and dynamics that support lipid droplet expansion
.
Cell Metab.
27
,
869
-
885.e6
.
Bernhard
,
W.
and
Rouiller
,
C.
(
1956
).
Close topographical relationship between mitochondria and ergastoplasm of liver cells in a definite phase of cellular activity
.
J. Biophys. Biochem. Cytol.
2
,
73
-
78
.
Bernhard
,
W.
,
Haguenau
,
F.
,
Gautier
,
A.
and
Oberling
,
C.
(
1952
).
[Submicroscopical structure of cytoplasmic basophils in the liver, pancreas and salivary gland; study of ultrafine slices by electron microscope]
.
Z. Zellforsch. Mikrosk. Anat.
37
,
281
-
300
.
Betz
,
C.
,
Stracka
,
D.
,
Prescianotto-Baschong
,
C.
,
Frieden
,
M.
,
Demaurex
,
N.
and
Hall
,
M. N.
(
2013
).
Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology
.
Proc. Natl. Acad. Sci. USA
110
,
12526
-
12534
.
Bonneau
,
B.
,
Ando
,
H.
,
Kawaai
,
K.
,
Hirose
,
M.
,
Takahashi-Iwanaga
,
H.
and
Mikoshiba
,
K.
(
2016
).
IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact
.
eLife
5
,
e19896
.
Boutant
,
M.
,
Kulkarni
,
S. S.
,
Joffraud
,
M.
,
Ratajczak
,
J.
,
Valera-Alberni
,
M.
,
Combe
,
R.
,
Zorzano
,
A.
and
Cantó
,
C.
(
2017
).
Mfn2 is critical for brown adipose tissue thermogenic function
.
EMBO J.
36
,
1543
-
1558
.
Boutry
,
M.
and
Kim
,
P. K.
(
2021
).
ORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division
.
Nat. Commun.
12
,
5354
.
Brar
,
K. K.
,
Hughes
,
D. T.
,
Morris
,
J. L.
,
Subramanian
,
K.
,
Krishna
,
S.
,
Gao
,
F.
,
Rieder
,
L. S.
,
Uhrig
,
S.
,
Freeman
,
J.
,
Smith
,
H. L.
et al.
(
2024
).
PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress
.
Science
385
,
eadp7114
.
Bravo
,
R.
,
Vicencio
,
J. M.
,
Parra
,
V.
,
Troncoso
,
R.
,
Munoz
,
J. P.
,
Bui
,
M.
,
Quiroga
,
C.
,
Rodriguez
,
A. E.
,
Verdejo
,
H. E.
,
Ferreira
,
J.
et al.
(
2011
).
Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress
.
J. Cell Sci.
124
,
2143
-
2152
.
Cantarero
,
L.
,
Juárez-Escoto
,
E.
,
Civera-Tregón
,
A.
,
Rodríguez-Sanz
,
M.
,
Roldán
,
M.
,
Benítez
,
R.
,
Hoenicka
,
J.
and
Palau
,
F.
(
2021
).
Mitochondria-lysosome membrane contacts are defective in GDAP1-related Charcot-Marie-Tooth disease
.
Hum. Mol. Genet.
29
,
3589
-
3605
.
Cantarero
,
L.
,
Garcia-Vargas
,
G.
,
Hoenicka
,
J.
and
Palau
,
F.
(
2023
).
Differential effects of Mendelian GDAP1 clinical variants on mitochondria-lysosome membrane contacts sites
.
Biol. Open
12
,
bio059707
.
Carpio
,
M. A.
,
Means
,
R. E.
,
Brill
,
A. L.
,
Sainz
,
A.
,
Ehrlich
,
B. E.
and
Katz
,
S. G.
(
2021
).
BOK controls apoptosis by Ca(2+) transfer through ER-mitochondrial contact sites
.
Cell Rep.
34
,
108827
.
Carreras-Sureda
,
A.
,
Jana
,
F.
,
Urra
,
H.
,
Durand
,
S.
,
Mortenson
,
D. E.
,
Sagredo
,
A.
,
Bustos
,
G.
,
Hazari
,
Y.
,
Ramos-Fernández
,
E.
,
Sassano
,
M. L.
et al.
(
2019
).
Non-canonical function of IRE1alpha determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics
.
Nat. Cell Biol.
21
,
755
-
767
.
Casanova
,
J. E.
and
Winckler
,
B.
(
2017
).
A new Rab7 effector controls phosphoinositide conversion in endosome maturation
.
J. Cell Biol.
216
,
2995
-
2997
.
Casas-Martinez
,
J. C.
,
Samali
,
A.
and
McDonagh
,
B.
(
2024
).
Redox regulation of UPR signalling and mitochondrial ER contact sites
.
Cell. Mol. Life Sci.
81
,
250
.
Cerqua
,
C.
,
Anesti
,
V.
,
Pyakurel
,
A.
,
Liu
,
D.
,
Naon
,
D.
,
Wiche
,
G.
,
Baffa
,
R.
,
Dimmer
,
K. S.
and
Scorrano
,
L.
(
2010
).
Trichoplein/mitostatin regulates endoplasmic reticulum-mitochondria juxtaposition
.
EMBO Rep.
11
,
854
-
860
.
Chakrabarti
,
R.
,
Ji
,
W. K.
,
Stan
,
R. V.
,
de Juan Sanz
,
J.
,
Ryan
,
T. A.
and
Higgs
,
H. N.
(
2018
).
INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division
.
J. Cell Biol.
217
,
251
-
268
.
Charman
,
M.
,
Kennedy
,
B. E.
,
Osborne
,
N.
and
Karten
,
B.
(
2010
).
MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein
.
J. Lipid Res.
51
,
1023
-
1034
.
Che
,
L.
,
Wu
,
J. S.
,
Xu
,
C. Y.
,
Cai
,
Y. X.
,
Lin
,
J. X.
,
Du
,
Z. B.
,
Shi
,
J. Z.
,
Han
,
T.
,
He
,
Y. Q.
,
Lin
,
Y. C.
et al.
(
2022
).
Protein phosphatase 2A-B56gamma-Drp1-Rab7 signaling axis regulates mitochondria-lysosome crosstalk to sensitize the anti-cancer therapy of hepatocellular carcinoma
.
Biochem. Pharmacol.
202
,
115132
.
Che
,
L.
,
Huang
,
J.
,
Lin
,
J. X.
,
Xu
,
C. Y.
,
Wu
,
X. M.
,
Du
,
Z. B.
,
Wu
,
J. S.
,
Lin
,
Z. N.
and
Lin
,
Y. C.
(
2023
).
Aflatoxin B1 exposure triggers hepatic lipotoxicity via p53 and perilipin 2 interaction-mediated mitochondria-lipid droplet contacts: An in vitro and in vivo assessment
.
J. Hazard. Mater.
445
,
130584
.
Chen
,
Y.
,
Csordas
,
G.
,
Jowdy
,
C.
,
Schneider
,
T. G.
,
Csordas
,
N.
,
Wang
,
W.
,
Liu
,
Y.
,
Kohlhaas
,
M.
,
Meiser
,
M.
,
Bergem
,
S.
et al.
(
2012
).
Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca(2+) crosstalk
.
Circ. Res.
111
,
863
-
875
.
Chu
,
Q.
,
Martinez
,
T. F.
,
Novak
,
S. W.
,
Donaldson
,
C. J.
,
Tan
,
D.
,
Vaughan
,
J. M.
,
Chang
,
T.
,
Diedrich
,
J. K.
,
Andrade
,
L.
,
Kim
,
A.
et al.
(
2019
).
Regulation of the ER stress response by a mitochondrial microprotein
.
Nat. Commun.
10
,
4883
.
Chung
,
J.
,
Torta
,
F.
,
Masai
,
K.
,
Lucast
,
L.
,
Czapla
,
H.
,
Tanner
,
L. B.
,
Narayanaswamy
,
P.
,
Wenk
,
M. R.
,
Nakatsu
,
F.
and
de Camilli
,
P.
(
2015
).
PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER-plasma membrane contacts
.
Science
349
,
428
-
432
.
Cioni
,
J. M.
,
Lin
,
J. Q.
,
Holtermann
,
A. V.
,
Koppers
,
M.
,
Jakobs
,
M. A. H.
,
Azizi
,
A.
,
Turner-Bridger
,
B.
,
Shigeoka
,
T.
,
Franze
,
K.
,
Harris
,
W. A.
et al.
(
2019
).
Late endosomes act as mRNA translation platforms and sustain mitochondria in axons
.
Cell
176
,
56
-
72.e15
.
Ciscato
,
F.
,
Filadi
,
R.
,
Masgras
,
I.
,
Pizzi
,
M.
,
Marin
,
O.
,
Damiano
,
N.
,
Pizzo
,
P.
,
Gori
,
A.
,
Frezzato
,
F.
,
Chiara
,
F.
et al.
(
2020
).
Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca(2+) -dependent death of cancer cells
.
EMBO Rep.
21
,
e49117
.
Cisneros
,
J.
,
Belton
,
T. B.
,
Shum
,
G. C.
,
Molakal
,
C. G.
and
Wong
,
Y. C.
(
2022
).
Mitochondria-lysosome contact site dynamics and misregulation in neurodegenerative diseases
.
Trends Neurosci.
45
,
312
-
322
.
Cosson
,
P.
,
Marchetti
,
A.
,
Ravazzola
,
M.
and
Orci
,
L.
(
2012
).
Mitofusin-2 independent juxtaposition of endoplasmic reticulum and mitochondria: an ultrastructural study
.
PLoS ONE
7
,
e46293
.
Crouzier
,
L.
,
Danese
,
A.
,
Yasui
,
Y.
,
Richard
,
E. M.
,
Lievens
,
J. C.
,
Patergnani
,
S.
,
Couly
,
S.
,
Diez
,
C.
,
Denus
,
M.
,
Cubedo
,
N.
et al.
(
2022
).
Activation of the sigma-1 receptor chaperone alleviates symptoms of Wolfram syndrome in preclinical models
.
Sci. Transl. Med.
14
,
eabh3763
.
Csordas
,
G.
,
Várnai
,
P.
,
Golenár
,
T.
,
Roy
,
S.
,
Purkins
,
G.
,
Schneider
,
T. G.
,
Balla
,
T.
and
Hajnóczky
,
G.
(
2010
).
Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface
.
Mol. Cell
39
,
121
-
132
.
Daniele
,
T.
,
Hurbain
,
I.
,
Vago
,
R.
,
Casari
,
G.
,
Raposo
,
G.
,
Tacchetti
,
C.
and
Schiaffino
,
M. V.
(
2014
).
Mitochondria and melanosomes establish physical contacts modulated by Mfn2 and involved in organelle biogenesis
.
Curr. Biol.
24
,
393
-
403
.
de Brito
,
O. M.
and
Scorrano
,
L.
(
2008
).
Mitofusin 2 tethers endoplasmic reticulum to mitochondria
.
Nature
456
,
605
-
610
.
de Ridder
,
I.
,
Kerkhofs
,
M.
,
Lemos
,
F. O.
,
Loncke
,
J.
,
Bultynck
,
G.
and
Parys
,
J. B.
(
2023
).
The ER-mitochondria interface, where Ca(2+) and cell death meet
.
Cell Calcium
112
,
102743
.
de Stefani
,
D.
,
Raffaello
,
A.
,
Teardo
,
E.
,
Szabò
,
I.
and
Rizzuto
,
R.
(
2011
).
A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter
.
Nature
476
,
336
-
340
.
de Vos
,
K. J.
,
Mórotz
,
G. M.
,
Stoica
,
R.
,
Tudor
,
E. L.
,
Lau
,
K. F.
,
Ackerley
,
S.
,
Warley
,
A.
,
Shaw
,
C. E.
and
Miller
,
C. C.
(
2012
).
VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis
.
Hum. Mol. Genet.
21
,
1299
-
1311
.
D'Eletto
,
M.
,
Rossin
,
F.
,
Occhigrossi
,
L.
,
Farrace
,
M. G.
,
Faccenda
,
D.
,
Desai
,
R.
,
Marchi
,
S.
,
Refolo
,
G.
,
Falasca
,
L.
,
Antonioli
,
M.
et al.
(
2018
).
Transglutaminase type 2 regulates ER-mitochondria contact sites by interacting with GRP75
.
Cell Rep.
25
,
3573
-
3581.e4
.
Desai
,
R.
,
East
,
D. A.
,
Hardy
,
L.
,
Faccenda
,
D.
,
Rigon
,
M.
,
Crosby
,
J.
,
Alvarez
,
M. S.
,
Singh
,
A.
,
Mainenti
,
M.
,
Hussey
,
L. K.
et al.
(
2020
).
Mitochondria form contact sites with the nucleus to couple prosurvival retrograde response
.
Sci. Adv.
6
,
eabc9955
.
Deus
,
C. M.
,
Yambire
,
K. F.
,
Oliveira
,
P. J.
and
Raimundo
,
N.
(
2020
).
Mitochondria-lysosome crosstalk: from physiology to neurodegeneration
.
Trends Mol. Med.
26
,
71
-
88
.
Doghman-Bouguerra
,
M.
,
Granatiero
,
V.
,
Sbiera
,
S.
,
Sbiera
,
I.
,
Lacas-Gervais
,
S.
,
Brau
,
F.
,
Fassnacht
,
M.
,
Rizzuto
,
R.
and
Lalli
,
E.
(
2016
).
FATE1 antagonizes calcium- and drug-induced apoptosis by uncoupling ER and mitochondria
.
EMBO Rep.
17
,
1264
-
1280
.
Dong
,
J.
,
Chen
,
L.
,
Ye
,
F.
,
Tang
,
J.
,
Liu
,
B.
,
Lin
,
J.
,
Zhou
,
P. H.
,
Lu
,
B.
,
Wu
,
M.
,
Lu
,
J. H.
et al.
(
2024
).
Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease
.
Nat. Commun.
15
,
168
.
Duan
,
C.
,
Liu
,
R.
,
Kuang
,
L.
,
Zhang
,
Z.
,
Hou
,
D.
,
Zheng
,
D.
,
Xiang
,
X.
,
Huang
,
H.
,
Liu
,
L.
and
Li
,
T.
(
2023
).
Activated Drp1 initiates the formation of endoplasmic reticulum-mitochondrial contacts via Shrm4-mediated actin bundling
.
Adv. Sci. (Weinh)
10
,
e2304885
.
Elbaz-Alon
,
Y.
,
Guo
,
Y.
,
Segev
,
N.
,
Harel
,
M.
,
Quinnell
,
D. E.
,
Geiger
,
T.
,
Avinoam
,
O.
,
Li
,
D.
and
Nunnari
,
J.
(
2020
).
PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria
.
Nat. Commun.
11
,
3645
.
Fan
,
H.
and
Tan
,
Y.
(
2024
).
Lipid droplet-mitochondria contacts in health and disease
.
Int. J. Mol. Sci.
25
,
6878
.
Fan
,
J.
,
Li
,
X.
,
Issop
,
L.
,
Culty
,
M.
and
Papadopoulos
,
V.
(
2016
).
ACBD2/ECI2-mediated peroxisome-mitochondria interactions in leydig cell steroid biosynthesis
.
Mol. Endocrinol.
30
,
763
-
782
.
Filadi
,
R.
,
Greotti
,
E.
,
Turacchio
,
G.
,
Luini
,
A.
,
Pozzan
,
T.
and
Pizzo
,
P.
(
2015
).
Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling
.
Proc. Natl. Acad. Sci. USA
112
,
E2174
-
E2181
.
Filadi
,
R.
,
Greotti
,
E.
,
Turacchio
,
G.
,
Luini
,
A.
,
Pozzan
,
T.
and
Pizzo
,
P.
(
2016
).
Presenilin 2 modulates endoplasmic reticulum-mitochondria coupling by tuning the antagonistic effect of Mitofusin 2
.
Cell Rep.
15
,
2226
-
2238
.
Filadi
,
R.
,
Leal
,
N. S.
,
Schreiner
,
B.
,
Rossi
,
A.
,
Dentoni
,
G.
,
Pinho
,
C. M.
,
Wiehager
,
B.
,
Cieri
,
D.
,
Calì
,
T.
,
Pizzo
P.
et al.
(
2018
).
TOM70 sustains cell bioenergetics by promoting IP3R3-mediated ER to mitochondria Ca2+ transfer
.
Curr. Biol.
28
,
369
-
382
.e6.
Freyre
,
C. A. C.
,
Rauher
,
P. C.
,
Ejsing
,
C. S.
and
Klemm
,
R. W.
(
2019
).
MIGA2 links mitochondria, the ER, and lipid droplets and promotes de novo lipogenesis in adipocytes
.
Mol. Cell
76
,
811
-
825.e14
.
Galmes
,
R.
,
Houcine
,
A.
,
Van Vliet
,
A. R.
,
Agostinis
,
P.
,
Jackson
,
C. L.
and
Giordano
,
F.
(
2016
).
ORP5/ORP8 localize to endoplasmic reticulum-mitochondria contacts and are involved in mitochondrial function
.
EMBO Rep.
17
,
800
-
810
.
Garcia Casas
,
P.
,
Rossini
,
M.
,
Påvénius
,
L.
,
Saeed
,
M.
,
Arnst
,
N.
,
Sonda
,
S.
,
Fernandes
,
T.
,
D'arsie
,
I.
,
Bruzzone
,
M.
,
Berno
,
V.
et al.
(
2024
).
Simultaneous detection of membrane contact dynamics and associated Ca(2+) signals by reversible chemogenetic reporters
.
Nat. Commun.
15
,
9775
.
Gerhold
,
J. M.
,
Cansiz-Arda
,
S.
,
Lõhmus
,
M.
,
Engberg
,
O.
,
Reyes
,
A.
,
Van Rennes
,
H.
,
Sanz
,
A.
,
Holt
,
I. J.
,
Cooper
,
H. M.
and
Spelbrink
,
J. N.
(
2015
).
Human mitochondrial DNA-protein complexes attach to a cholesterol-rich membrane structure
.
Sci. Rep.
5
,
15292
.
Giacomello
,
M.
and
Pellegrini
,
L.
(
2016
).
The coming of age of the mitochondria-ER contact: a matter of thickness
.
Cell Death Differ.
23
,
1417
-
1427
.
Giacomello
,
M.
,
Drago
,
I.
,
Bortolozzi
,
M.
,
Scorzeto
,
M.
,
Gianelle
,
A.
,
Pizzo
,
P.
and
Pozzan
,
T.
(
2010
).
Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of store-operated Ca2+ channels
.
Mol. Cell
38
,
280
-
290
.
Gilquin
,
B.
,
Taillebourg
,
E.
,
Cherradi
,
N.
,
Hubstenberger
,
A.
,
Gay
,
O.
,
Merle
,
N.
,
Assard
,
N.
,
Fauvarque
,
M. O.
,
Tomohiro
,
S.
,
Kuge
,
O.
et al.
(
2010
).
The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes
.
Mol. Cell. Biol.
30
,
1984
-
1996
.
Göbel
,
J.
,
Engelhardt
,
E.
,
Pelzer
,
P.
,
Sakthivelu
,
V.
,
Jahn
,
H. M.
,
Jevtic
,
M.
,
Folz-Donahue
,
K.
,
Kukat
,
C.
,
Schauss
,
A.
,
Frese
,
C. K.
et al.
(
2020
).
Mitochondria-endoplasmic reticulum contacts in reactive astrocytes promote vascular remodeling
.
Cell Metab.
31
,
791
-
808.e8
.
Gomez-Suaga
,
P.
,
Paillusson
,
S.
,
Stoica
,
R.
,
Noble
,
W.
,
Hanger
,
D. P.
and
Miller
,
C. C. J.
(
2017
).
The ER-mitochondria tethering complex VAPB-PTPIP51 regulates autophagy
.
Curr. Biol.
27
,
371
-
385
.
Gomez-Suaga
,
P.
,
Pérez-Nievas
,
B. G.
,
Glennon
,
E. B.
,
Lau
,
D. H. W.
,
Paillusson
,
S.
,
Mórotz
,
G. M.
,
Calì
,
T.
,
Pizzo
,
P.
,
Noble
,
W.
and
Miller
,
C. C. J.
(
2019
).
The VAPB-PTPIP51 endoplasmic reticulum-mitochondria tethering proteins are present in neuronal synapses and regulate synaptic activity
.
Acta Neuropathol. Commun.
7
,
35
.
Gordaliza-Alaguero
,
I.
,
Cantó
,
C.
and
Zorzano
,
A.
(
2019
).
Metabolic implications of organelle-mitochondria communication
.
EMBO Rep.
20
,
e47928
.
Guillen-Samander
,
A.
,
Leonzino
,
M.
,
Hanna
,
M. G.
,
Tang
,
N.
,
Shen
,
H.
and
De Camilli
,
P.
(
2021
).
VPS13D bridges the ER to mitochondria and peroxisomes via Miro
.
J. Cell Biol.
220
,
e202010004
.
Gutierrez
,
T.
,
Qi
,
H.
,
Yap
,
M. C.
,
Tahbaz
,
N.
,
Milburn
,
L. A.
,
Lucchinetti
,
E.
,
Lou
,
P. H.
,
Zaugg
,
M.
,
Lapointe
,
P. G.
,
Mercier
,
P.
et al.
(
2020
).
The ER chaperone calnexin controls mitochondrial positioning and respiration
.
Sci. Signal.
13
,
eaax6660
.
Guyard
,
V.
,
Monteiro-Cardoso
,
V. F.
,
Omrane
,
M.
,
Sauvanet
,
C.
,
Houcine
,
A.
,
Boulogne
,
C.
,
Ben Mbarek
,
K.
,
Vitale
,
N.
,
Faklaris
,
O.
,
El Khallouki
,
N.
et al.
(
2022
).
ORP5 and ORP8 orchestrate lipid droplet biogenesis and maintenance at ER-mitochondria contact sites
.
J. Cell Biol.
221
,
e202112107
.
Hamasaki
,
M.
,
Furuta
,
N.
,
Matsuda
,
A.
,
Nezu
,
A.
,
Yamamoto
,
A.
,
Fujita
,
N.
,
Oomori
,
H.
,
Noda
,
T.
,
Haraguchi
,
T.
,
Hiraoka
,
Y.
et al.
(
2013
).
Autophagosomes form at ER-mitochondria contact sites
.
Nature
495
,
389
-
393
.
Han
,
Y.
,
Li
,
M.
,
Qiu
,
F.
,
Zhang
,
M.
and
Zhang
,
Y. H.
(
2017
).
Cell-permeable organic fluorescent probes for live-cell long-term super-resolution imaging reveal lysosome-mitochondrion interactions
.
Nat. Commun.
8
,
1307
.
Hayashi
,
T.
and
Su
,
T. P.
(
2007
).
Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival
.
Cell
131
,
596
-
610
.
He
,
J.
,
Mao
,
C. C.
,
Reyes
,
A.
,
Sembongi
,
H.
,
Di Re
,
M.
,
Granycome
,
C.
,
Clippingdale
,
A. B.
,
Fearnley
,
I. M.
,
Harbour
,
M.
,
Robinson
,
A. J.
et al.
(
2007
).
The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization
.
J. Cell Biol.
176
,
141
-
146
.
Hirabayashi
,
Y.
,
Kwon
,
S. K.
,
Paek
,
H.
,
Pernice
,
W. M.
,
Paul
,
M. A.
,
Lee
,
J.
,
Erfani
,
P.
,
Raczkowski
,
A.
,
Petrey
,
D. S.
,
Pon
,
L. A.
et al.
(
2017
).
ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons
.
Science
358
,
623
-
630
.
Hoglinger
,
D.
,
Burgoyne
,
T.
,
Sanchez-Heras
,
E.
,
Hartwig
,
P.
,
Colaco
,
A.
,
Newton
,
J.
,
Futter
,
C. E.
,
Spiegel
,
S.
,
Platt
,
F. M.
and
Eden
,
E. R.
(
2019
).
NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress
.
Nat. Commun.
10
,
4276
.
Honscher
,
C.
,
Mari
,
M.
,
Auffarth
,
K.
,
Bohnert
,
M.
,
Griffith
,
J.
,
Geerts
,
W.
,
van der Laan
,
M.
,
Cabrera
,
M.
,
Reggiori
,
F.
and
Ungermann
,
C.
(
2014
).
Cellular metabolism regulates contact sites between vacuoles and mitochondria
.
Dev. Cell
30
,
86
-
94
.
Huh
,
J. Y.
,
Reilly
,
S. M.
,
Abu-Odeh
,
M.
,
Murphy
,
A. N.
,
Mahata
,
S. K.
,
Zhang
,
J.
,
Cho
,
Y.
,
Seo
,
J. B.
,
Hung
,
C. W.
,
Green
,
C. R.
et al.
(
2020
).
TANK-binding kinase 1 regulates the localization of acyl-CoA synthetase ACSL1 to control hepatic fatty acid oxidation
.
Cell Metab.
32
,
1012
-
1027.e7
.
Hung
,
V.
,
Lam
,
S. S.
,
Udeshi
,
N. D.
,
Svinkina
,
T.
,
Guzman
,
G.
,
Mootha
,
V. K.
,
Carr
,
S. A.
and
Ting
,
A. Y.
(
2017
).
Proteomic mapping of cytosol-facing outer mitochondrial and ER membranes in living human cells by proximity biotinylation
.
eLife
6
,
e24463
.
Huo
,
Y.
,
Sun
,
W.
,
Shi
,
T.
,
Gao
,
S.
and
Zhuang
,
M.
(
2022
).
The MFN1 and MFN2 mitofusins promote clustering between mitochondria and peroxisomes
.
Commun. Biol.
5
,
423
.
Issop
,
L.
,
Fan
,
J.
,
Lee
,
S.
,
Rone
,
M. B.
,
Basu
,
K.
,
Mui
,
J.
and
Papadopoulos
,
V.
(
2015
).
Mitochondria-associated membrane formation in hormone-stimulated Leydig cell steroidogenesis: role of ATAD3
.
Endocrinology
156
,
334
-
345
.
Itoh
,
K.
,
Adachi
,
Y.
,
Yamada
,
T.
,
Suzuki
,
T. L.
,
Otomo
,
T.
,
McBride
,
H. M.
,
Yoshimori
,
T.
,
Iijima
,
M.
and
Sesaki
,
H.
(
2018
).
A brain-enriched Drp1 isoform associates with lysosomes, late endosomes, and the plasma membrane
.
J. Biol. Chem.
293
,
11809
-
11822
.
Iwasawa
,
R.
,
Mahul-Mellier
,
A. L.
,
Datler
,
C.
,
Pazarentzos
,
E.
and
Grimm
,
S.
(
2011
).
Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction
.
EMBO J.
30
,
556
-
568
.
Jagerstrom
,
S.
,
Polesie
,
S.
,
Wickström
,
Y.
,
Johansson
,
B. R.
,
Schroder
,
H. D.
,
Hojlund
,
K.
and
Bostrom
,
P.
(
2009
).
Lipid droplets interact with mitochondria using SNAP23
.
Cell Biol. Int.
33
,
934
-
940
.
Janer
,
A.
,
Morris
,
J. L.
,
Krols
,
M.
,
Antonicka
,
H.
,
Aaltonen
,
M. J.
,
Lin
,
Z.-Y.
,
Gingras
,
A.-C.
,
Prudent
,
J.
and
Shoubridge
,
E. A.
(
2024
).
ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis
.
Life Sci. Alliance
7
,
e2023010075
.
Joseph
,
S. K.
,
Young
,
M. P.
,
Alzayady
,
K.
,
Yule
,
D. I.
,
Ali
,
M.
,
Booth
,
D. M.
and
Hajnóczky
,
G.
(
2018
).
Redox regulation of type-I inositol trisphosphate receptors in intact mammalian cells
.
J. Biol. Chem.
293
,
17464
-
17476
.
Katona
,
M.
,
Bartok
,
A.
,
Nichtova
,
Z.
,
Csordás
,
G.
,
Berezhnaya
,
E.
,
Weaver
,
D.
,
Ghosh
,
A.
,
Várnai
,
P.
,
Yule
,
D. I.
and
Hajnóczky
,
G.
(
2022
).
Capture at the ER-mitochondrial contacts licenses IP(3) receptors to stimulate local Ca(2+) transfer and oxidative metabolism
.
Nat. Commun.
13
,
6779
.
Kaushik
,
S.
and
Cuervo
,
A. M.
(
2015
).
Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis
.
Nat. Cell Biol.
17
,
759
-
770
.
Khalil
,
S.
,
Holy
,
M.
,
Grado
,
S.
,
Fleming
,
R.
,
Kurita
,
R.
,
Nakamura
,
Y.
and
Goldfarb
,
A.
(
2017
).
A specialized pathway for erythroid iron delivery through lysosomal trafficking of transferrin receptor 2
.
Blood Adv.
1
,
1181
-
1194
.
Kim
,
S.
,
Wong
,
Y. C.
,
Gao
,
F.
and
Krainc
,
D.
(
2021
).
Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson's disease
.
Nat. Commun.
12
,
1807
.
Kim
,
H.
,
Lee
,
S.
,
Jun
,
Y.
and
Lee
,
C.
(
2022
).
Structural basis for mitoguardin-2 mediated lipid transport at ER-mitochondrial membrane contact sites
.
Nat. Commun.
13
,
3702
.
Koch
,
J.
,
Pranjic
,
K.
,
Huber
,
A.
,
Ellinger
,
A.
,
Hartig
,
A.
,
Kragler
,
F.
and
Brocard
,
C.
(
2010
).
PEX11 family members are membrane elongation factors that coordinate peroxisome proliferation and maintenance
.
J. Cell Sci.
123
,
3389
-
3400
.
Kornmann
,
B.
,
Currie
,
E.
,
Collins
,
S. R.
,
Schuldiner
,
M.
,
Nunnari
,
J.
,
Weissman
,
J. S.
and
Walter
,
P.
(
2009
).
An ER-mitochondria tethering complex revealed by a synthetic biology screen
.
Science
325
,
477
-
481
.
Kumar
,
N.
,
Leonzino
,
M.
,
Hancock-Cerutti
,
W.
,
Horenkamp
,
F. A.
,
Li
,
P.
,
Lees
,
J. A.
,
Wheeler
,
H.
,
Reinisch
,
K. M.
and
De Camilli
,
P.
(
2018
).
VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites
.
J. Cell Biol.
217
,
3625
-
3639
.
Kuo
,
I. Y.
,
Brill
,
A. L.
,
Lemos
,
F. O.
,
Jiang
,
J. Y.
,
Falcone
,
J. L.
,
Kimmerling
,
E. P.
,
Cai
,
Y.
,
Dong
,
K.
,
Kaplan
,
D. L.
,
Wallace
,
D. P.
et al.
(
2019
).
Polycystin 2 regulates mitochondrial Ca(2+) signaling, bioenergetics, and dynamics through mitofusin 2
.
Sci. Signal.
12
,
eaat7397
.
Kustatscher
,
G.
,
Grabowski
,
P.
,
Schrader
,
T. A.
,
Passmore
,
J. B.
,
Schrader
,
M.
and
Rappsilber
,
J.
(
2019
).
Co-regulation map of the human proteome enables identification of protein functions
.
Nat. Biotechnol.
37
,
1361
-
1371
.
Leal
,
N. S.
,
Schreiner
,
B.
,
Pinho
,
C. M.
,
Filadi
,
R.
,
Wiehager
,
B.
,
Karlström
,
H.
,
Pizzo
,
P.
and
Ankarcrona
,
M.
(
2016
).
Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid beta-peptide production
.
J. Cell. Mol. Med.
20
,
1686
-
1695
.
Lewis
,
J. A.
and
Tata
,
J. R.
(
1973
).
A rapidly sedimenting fraction of rat liver endoplasmic reticulum
.
J. Cell Sci.
13
,
447
-
459
.
Li
,
D.
,
Li
,
X.
,
Guan
,
Y.
and
Guo
,
X.
(
2015
).
Mitofusin-2-mediated tethering of mitochondria and endoplasmic reticulum promotes cell cycle arrest of vascular smooth muscle cells in G0/G1 phase
.
Acta Biochim. Biophys. Sin. (Shanghai)
47
,
441
-
450
.
Liao
,
X.
,
Zhu
,
S.
,
Qiu
,
S.
,
Cao
,
H.
,
Jiang
,
W.
,
Xu
,
H.
,
Sun
,
Y.
and
Zheng
,
B.
(
2024
).
Mfn2 regulates mitochondria-associated ER membranes to affect PCOS oocyte development
.
Endocr. Connect.
13
,
e230343
.
Lim
,
Y.
,
Cho
,
I. T.
,
Schoel
,
L. J.
,
Cho
,
G.
and
Golden
,
J. A.
(
2015
).
Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts
.
Ann. Neurol.
78
,
679
-
696
.
Lin
,
J. X.
,
Xu
,
C. Y.
,
Wu
,
X. M.
,
Che
,
L.
,
Li
,
T. Y.
,
Mo
,
S. M.
,
Guo
,
D. B.
,
Lin
,
Z. N.
and
Lin
,
Y. C.
(
2023
).
Rab7a-mTORC1 signaling-mediated cholesterol trafficking from the lysosome to mitochondria ameliorates hepatic lipotoxicity induced by aflatoxin B1 exposure
.
Chemosphere
320
,
138071
.
Liu
,
Y.
,
Ma
,
X.
,
Fujioka
,
H.
,
Liu
,
J.
,
Chen
,
S.
and
Zhu
,
X.
(
2019
).
DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1
.
Proc. Natl. Acad. Sci. USA
116
,
25322
-
25328
.
Loncke
,
J.
,
Kaasik
,
A.
,
Bezprozvanny
,
I.
,
Parys
,
J. B.
,
Kerkhofs
,
M.
and
Bultynck
,
G.
(
2021
).
Balancing ER-mitochondrial Ca(2+) fluxes in health and disease
.
Trends Cell Biol.
31
,
598
-
612
.
Loncke
,
J.
,
De Ridder
,
I.
,
Kale
,
J.
,
Wagner
,
L.
,
Kaasik
,
A.
,
Parys
,
J. B.
,
Kerkhofs
,
M.
,
Andrews
,
D. W.
,
Yule
,
D.
,
Vervliet
,
T.
et al.
(
2025
).
CISD2 counteracts the inhibition of ER-mitochondrial calcium transfer by anti-apoptotic BCL-2
.
Biochim. Biophys. Acta Mol. Cell Res.
1872
,
119857
.
Losón
,
O. C.
,
Song
,
Z.
,
Chen
,
H.
and
Chan
,
D. C.
(
2013
).
Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission
.
Mol. Biol. Cell
24
,
659
-
667
.
Lucendo
,
E.
,
Sancho
,
M.
,
Lolicato
,
F.
,
Javanainen
,
M.
,
Kulig
,
W.
,
Leiva
,
D.
,
Duart
,
G.
,
Andreu-Fernandez
,
V.
,
Mingarro
,
I.
and
Orzáez
,
M.
(
2020
).
Mcl-1 and Bok transmembrane domains: unexpected players in the modulation of apoptosis
.
Proc. Natl. Acad. Sci. USA
117
,
27980
-
27988
.
Maddison
,
D. C.
,
Malik
,
B.
,
Amadio
,
L.
,
Bis-Brewer
,
D. M.
,
Zuchner
,
S.
,
Peters
,
O. M.
and
Smith
,
G. A.
(
2023
).
COPI-regulated mitochondria-ER contact site formation maintains axonal integrity
.
Cell Rep
42
,
112883
.
Makio
,
T.
and
Simmen
,
T.
(
2024
).
Not so rare: diseases based on mutant proteins controlling endoplasmic reticulum-mitochondria contact (MERC) tethering
.
Contact (Thousand Oaks)
7
,
25152564241261228
.
Manor
,
U.
,
Bartholomew
,
S.
,
Golani
,
G.
,
Christenson
,
E.
,
Kozlov
,
M.
,
Higgs
,
H.
,
Spudich
,
J.
and
Lippincott-Schwartz
,
J.
(
2015
).
A mitochondria-anchored isoform of the actin-nucleating spire protein regulates mitochondrial division
.
eLife
4
,
e08828
.
Matsuzaki
,
H.
,
Fujimoto
,
T.
,
Tanaka
,
M.
and
Shirasawa
,
S.
(
2013
).
Tespa1 is a novel component of mitochondria-associated endoplasmic reticulum membranes and affects mitochondrial calcium flux
.
Biochem. Biophys. Res. Commun.
433
,
322
-
326
.
Miner
,
G. E.
,
So
,
C. M.
,
Edwards
,
W.
,
Ragusa
,
J. V.
,
Wine
,
J. T.
,
Wong Gutierrez
,
D.
,
Airola
,
M. V.
,
Herring
,
L. E.
,
Coleman
,
R. A.
,
Klett
,
E. L.
et al.
(
2023
).
PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport
.
Dev. Cell
58
,
1250
-
1265.e6
.
Modi
,
S.
,
Lopez-Domenech
,
G.
,
Halff
,
E. F.
,
Covill-Cooke
,
C.
,
Ivankovic
,
D.
,
Melandri
,
D.
,
Arancibia-Cárcamo
,
I. L.
,
Burden
,
J. J.
,
Lowe
,
A. R.
and
Kittler
,
J. T.
(
2019
).
Miro clusters regulate ER-mitochondria contact sites and link cristae organization to the mitochondrial transport machinery
.
Nat. Commun.
10
,
4399
.
Monteiro-Cardoso
,
V. F.
,
Rochin
,
L.
,
Arora
,
A.
,
Houcine
,
A.
,
Jaaskelainen
,
E.
,
Kivela
,
A. M.
,
Sauvanet
,
C.
,
Le Bars
,
R.
,
Marien
,
E.
,
Dehairs
,
J.
et al.
(
2022
).
ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine
.
Cell Rep.
40
,
111364
.
Morcillo
,
P.
,
Kabra
,
K.
,
Velasco
,
K.
,
Cordero
,
H.
,
Jennings
,
S.
,
Yun
,
T. D.
,
Larrea
,
D.
,
Akman
,
H. O.
and
Schon
,
E. A.
(
2024
).
Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease
.
Cell Death Dis.
15
,
405
.
Mori
,
T.
,
Hayashi
,
T.
,
Hayashi
,
E.
and
Su
,
T. P.
(
2013
).
Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival
.
PLoS ONE
8
,
e76941
.
Moulis
,
M.
,
Grousset
,
E.
,
Faccini
,
J.
,
Richetin
,
K.
,
Thomas
,
G.
and
Vindis
,
C.
(
2019
).
The multifunctional sorting protein PACS-2 controls mitophagosome formation in human vascular smooth muscle cells through mitochondria-ER contact sites
.
Cells
8
,
638
.
Myhill
,
N.
,
Lynes
,
E. M.
,
Nanji
,
J. A.
,
Blagoveshchenskaya
,
A. D.
,
Fei
,
H.
,
Carmine Simmen
,
K.
,
Cooper
,
T. J.
,
Thomas
,
G.
and
Simmen
,
T.
(
2008
).
The subcellular distribution of calnexin is mediated by PACS-2
.
Mol. Biol. Cell
19
,
2777
-
2788
.
Nagashima
,
S.
,
Tabara
,
L. C.
,
Tilokani
,
L.
,
Paupe
,
V.
,
Anand
,
H.
,
Pogson
,
J. H.
,
Zunino
,
R.
,
McBride
,
H. M.
and
Prudent
,
J.
(
2020
).
Golgi-derived PI(4)P-containing vesicles drive late steps of mitochondrial division
.
Science
367
,
1366
-
1371
.
Nakamura
,
K.
,
Aoyama-Ishiwatari
,
S.
,
Nagao
,
T.
,
Paaran
,
M.
,
Obara
,
C. J.
,
Sakurai-Saito
,
Y.
,
Johnston
,
J.
,
Du
,
Y.
,
Suga
,
S.
,
Tsuboi
,
M.
et al.
(
2025
).
Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering
.
Nat. Commun.
16
,
3401
.
Namba
,
T.
(
2019
).
BAP31 regulates mitochondrial function via interaction with Tom40 within ER-mitochondria contact sites
.
Sci. Adv.
5
,
eaaw1386
.
Namba
,
T.
,
Tian
,
F.
,
Chu
,
K.
,
Hwang
,
S. Y.
,
Yoon
,
K. W.
,
Byun
,
S.
,
Hiraki
,
M.
,
Mandinova
,
A.
and
Lee
,
S. W.
(
2013
).
CDIP1-BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under endoplasmic reticulum stress
.
Cell Rep.
5
,
331
-
339
.
Naon
,
D.
,
Zaninello
,
M.
,
Giacomello
,
M.
,
Varanita
,
T.
,
Grespi
,
F.
,
Lakshminaranayan
,
S.
,
Serafini
,
A.
,
Semenzato
,
M.
,
Herkenne
,
S.
,
Hernandez-Alvarez
,
M. I.
et al.
(
2016
).
Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether
.
Proc. Natl. Acad. Sci. USA
113
,
11249
-
11254
.
Naon
,
D.
,
Hernandez-Alvarez
,
M. I.
,
Shinjo
,
S.
,
Wieczor
,
M.
,
Ivanova
,
S.
,
Martins De Brito
,
O.
,
Quintana
,
A.
,
Hidalgo
,
J.
,
Palacin
,
M.
,
Aparicio
,
P.
et al.
(
2023
).
Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria
.
Science
380
,
eadh9351
.
Nolden
,
K. A.
,
Harwig
,
M. C.
and
Hill
,
R. B.
(
2023
).
Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission
.
J. Biol. Chem.
299
,
105380
.
Obara
,
C. J.
,
Nixon-Abell
,
J.
,
Moore
,
A. S.
,
Riccio
,
F.
,
Hoffman
,
D. P.
,
Shtengel
,
G.
,
Xu
,
C. S.
,
Schaefer
,
K.
,
Pasolli
,
H. A.
,
Masson
,
J. B.
et al.
(
2024
).
Motion of VAPB molecules reveals ER-mitochondria contact site subdomains
.
Nature
626
,
169
-
176
.
Onoue
,
K.
,
Jofuku
,
A.
,
Ban-Ishihara
,
R.
,
Ishihara
,
T.
,
Maeda
,
M.
,
Koshiba
,
T.
,
Itoh
,
T.
,
Fukuda
,
M.
,
Otera
,
H.
,
Oka
,
T.
et al.
(
2013
).
Fis1 acts as a mitochondrial recruitment factor for TBC1D15 that is involved in regulation of mitochondrial morphology
.
J. Cell Sci.
126
,
176
-
185
.
Ouyang
,
Q.
,
Chen
,
Q.
,
Ke
,
S.
,
Ding
,
L.
,
Yang
,
X.
,
Rong
,
P.
,
Feng
,
W.
,
Cao
,
Y.
,
Wang
,
Q.
,
Li
,
M.
et al.
(
2023
).
Rab8a as a mitochondrial receptor for lipid droplets in skeletal muscle
.
Dev. Cell
58
,
289
-
305.e6
.
Pan
,
X.
,
Ren
,
L.
,
Yang
,
Y.
,
Xu
,
Y.
,
Ning
,
L.
,
Zhang
,
Y.
,
Luo
,
H.
,
Zou
,
Q.
and
Zhang
,
Y.
(
2024
).
MCSdb, a database of proteins residing in membrane contact sites
.
Sci. Data
11
,
281
.
Patergnani
,
S.
,
Bataillard
,
M. S.
,
Danese
,
A.
,
Alves
,
S.
,
Cazevieille
,
C.
,
Valero
,
R.
,
Tranebjaerg
,
L.
,
Maurice
,
T.
,
Pinton
,
P.
,
Delprat
,
B.
et al.
(
2024
).
The Wolfram-like variant WFS1(E864K) destabilizes MAM and compromises autophagy and mitophagy in human and mice
.
Autophagy
20
,
2055
-
2066
.
Peng
,
W.
,
Wong
,
Y. C.
and
Krainc
,
D.
(
2020
).
Mitochondria-lysosome contacts regulate mitochondrial Ca(2+) dynamics via lysosomal TRPML1
.
Proc. Natl. Acad. Sci. USA
117
,
19266
-
19275
.
Peng
,
W.
,
Schröder
,
L. F.
,
Song
,
P.
,
Wong
,
Y. C.
and
Krainc
,
D.
(
2023
).
Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease
.
Sci. Adv.
9
,
eadh3347
.
Perrone
,
M.
,
Caroccia
,
N.
,
Genovese
,
I.
,
Missiroli
,
S.
,
Modesti
,
L.
,
Pedriali
,
G.
,
Vezzani
,
B.
,
Vitto
,
V. A. M.
,
Antenori
,
M.
,
Lebiedzinska-Arciszewska
,
M.
et al.
(
2020
).
The role of mitochondria-associated membranes in cellular homeostasis and diseases
.
Int. Rev. Cell Mol. Biol.
350
,
119
-
196
.
Posor
,
Y.
,
Jang
,
W.
and
Haucke
,
V.
(
2022
).
Phosphoinositides as membrane organizers
.
Nat. Rev. Mol. Cell Biol.
23
,
797
-
816
.
Rigoni
,
G.
,
Calvo
,
E.
,
Glytsou
,
C.
,
Carro-Alvarellos
,
M.
,
Noguchi
,
M.
,
Semenzato
,
M.
,
Quirin
,
C.
,
Caicci
,
F.
,
Meneghetti
,
N.
,
Sturlese
,
M.
et al.
(
2025
).
MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling
.
Cell Metab.
37
,
1024
-
1038.e8
.
Rizzollo
,
F.
and
Agostinis
,
P.
(
2025
).
Mitochondria-lysosome contact sites: emerging players in cellular homeostasis and disease
.
Contact (Thousand Oaks)
8
,
25152564251329250
.
Rizzuto
,
R.
,
Pinton
,
P.
,
Carrington
,
W.
,
Fay
,
F. S.
,
Fogarty
,
K. E.
,
Lifshitz
,
L. M.
,
Tuft
,
R. A.
and
Pozzan
,
T.
(
1998
).
Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses
.
Science
280
,
1763
-
1766
.
Saheki
,
Y.
and
De Camilli
,
P.
(
2017
).
The extended-synaptotagmins
.
Biochim. Biophys. Acta Mol. Cell Res.
1864
,
1490
-
1493
.
Sammels
,
E.
,
Devogelaere
,
B.
,
Mekahli
,
D.
,
Bultynck
,
G.
,
Missiaen
,
L.
,
Parys
,
J. B.
,
Cai
,
Y.
,
Somlo
,
S.
and
De Smedt
,
H.
(
2010
).
Polycystin-2 activation by inositol 1,4,5-trisphosphate-induced Ca2+ release requires its direct association with the inositol 1,4,5-trisphosphate receptor in a signaling microdomain
.
J. Biol. Chem.
285
,
18794
-
18805
.
Sassano
,
M. L.
,
Felipe-Abrio
,
B.
and
Agostinis
,
P.
(
2022
).
ER-mitochondria contact sites; a multifaceted factory for Ca(2+) signaling and lipid transport
.
Front. Cell Dev. Biol.
10
,
988014
.
Sassano
,
M. L.
,
Van Vliet
,
A. R.
,
Vervoort
,
E.
,
Van Eygen
,
S.
,
Van Den Haute
,
C.
,
Pavie
,
B.
,
Roels
,
J.
,
Swinnen
,
J. V.
,
Spinazzi
,
M.
,
Moens
,
L.
et al.
(
2023
).
PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration
.
J. Cell Biol.
222
,
e202206008
.
Schneeberger
,
M.
,
Dietrich
,
M. O.
,
Sebastian
,
D.
,
Imbernón
,
M.
,
Castaño
,
C.
,
Garcia
,
A.
,
Esteban
,
Y.
,
Gonzalez-Franquesa
,
A.
,
Rodríguez
,
I. C.
,
Bortolozzi
,
A.
et al.
(
2013
).
Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance
.
Cell
155
,
172
-
187
.
Schrader
,
T. A.
,
Carmichael
,
R. E.
,
Islinger
,
M.
,
Costello
,
J. L.
,
Hacker
,
C.
,
Bonekamp
,
N. A.
,
Weishaupt
,
J. H.
,
Andersen
,
P. M.
and
Schrader
,
M.
(
2022
).
PEX11beta and FIS1 cooperate in peroxisome division independently of mitochondrial fission factor
.
J. Cell Sci.
135
,
jcs259924
.
Scorrano
,
L.
,
De Matteis
,
M. A.
,
Emr
,
S.
,
Giordano
,
F.
,
Hajnoczky
,
G.
,
Kornmann
,
B.
,
Lackner
,
L. L.
,
Levine
,
T. P.
,
Pellegrini
,
L.
,
Reinisch
,
K.
et al.
(
2019
).
Coming together to define membrane contact sites
.
Nat. Commun.
10
,
1287
.
Sebastian
,
D.
,
Hernández-Alvarez
,
M. I.
,
Segalés
,
J.
,
Sorianello
,
E.
,
Muñoz
,
J. P.
,
Sala
,
D.
,
Waget
,
A.
,
Liesa
,
M.
,
Paz
,
J. C.
,
Gopalacharyulu
,
P.
et al.
(
2012
).
Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis
.
Proc. Natl. Acad. Sci. USA
109
,
5523
-
5528
.
Shiiba
,
I.
,
Ito
,
N.
,
Oshio
,
H.
,
Ishikawa
,
Y.
,
Nagao
,
T.
,
Shimura
,
H.
,
Oh
,
K. W.
,
Takasaki
,
E.
,
Yamaguchi
,
F.
,
Konagaya
,
R.
et al.
(
2025
).
ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress
.
Nat. Commun.
16
,
1508
.
Shirane
,
M.
,
Wada
,
M.
,
Morita
,
K.
,
Hayashi
,
N.
,
Kunimatsu
,
R.
,
Matsumoto
,
Y.
,
Matsuzaki
,
F.
,
Nakatsumi
,
H.
,
Ohta
,
K.
,
Tamura
,
Y.
et al.
(
2020
).
Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation
.
Nat. Commun.
11
,
4576
.
Shore
,
G. C.
and
Tata
,
J. R.
(
1977
).
Two fractions of rough endoplasmic reticulum from rat liver. I. Recovery of rapidly sedimenting endoplasmic reticulum in association with mitochondria
.
J. Cell Biol.
72
,
714
-
725
.
Simmen
,
T.
,
Aslan
,
J. E.
,
Blagoveshchenskaya
,
A. D.
,
Thomas
,
L.
,
Wan
,
L.
,
Xiang
,
Y.
,
Feliciangeli
,
S. F.
,
Hung
,
C. H.
,
Crump
,
C. M.
and
Thomas
,
G.
(
2005
).
PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis
.
EMBO J.
24
,
717
-
729
.
Sood
,
A.
,
Jeyaraju
,
D. V.
,
Prudent
,
J.
,
Caron
,
A.
,
Lemieux
,
P.
,
McBride
,
H. M.
,
Laplante
,
M.
,
Toth
,
K.
and
Pellegrini
,
L.
(
2014
).
A Mitofusin-2-dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver
.
Proc. Natl. Acad. Sci. USA
111
,
16017
-
16022
.
Stone
,
S. J.
,
Levin
,
M. C.
,
Zhou
,
P.
,
Han
,
J.
,
Walther
,
T. C.
and
Farese
,
R. V.
Jr.
(
2009
).
The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria
.
J. Biol. Chem.
284
,
5352
-
5361
.
Subramani
,
S.
,
Shukla
,
N.
and
Farre
,
J. C.
(
2023
).
Convergent and divergent mechanisms of peroxisomal and mitochondrial division
.
J. Cell Biol.
222
,
e202304076
.
Sugiura
,
A.
,
Nagashima
,
S.
,
Tokuyama
,
T.
,
Amo
,
T.
,
Matsuki
,
Y.
,
Ishido
,
S.
,
Kudo
,
Y.
,
McBride
,
H. M.
,
Fukuda
,
T.
,
Matsushita
,
N.
et al.
(
2013
).
MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2
.
Mol. Cell
51
,
20
-
34
.
Sun
,
S.
,
Yu
,
W.
,
Xu
,
H.
,
Li
,
C.
,
Zou
,
R.
,
Wu
,
N. N.
,
Wang
,
L.
,
Ge
,
J.
,
Ren
,
J.
and
Zhang
,
Y.
(
2022
).
TBC1D15-Drp1 interaction-mediated mitochondrial homeostasis confers cardioprotection against myocardial ischemia/reperfusion injury
.
Metabolism
134
,
155239
.
Szabadkai
,
G.
,
Bianchi
,
K.
,
Várnai
,
P.
,
De Stefani
,
D.
,
Wieckowski
,
M. R.
,
Cavagna
,
D.
,
Nagy
,
A. I.
,
Balla
,
T.
and
Rizzuto
,
R.
(
2006
).
Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels
.
J. Cell Biol.
175
,
901
-
911
.
Tang
,
Z.
,
Takahashi
,
Y.
,
He
,
H.
,
Hattori
,
T.
,
Chen
,
C.
,
Liang
,
X.
,
Chen
,
H.
,
Young
,
M. M.
and
Wang
,
H. G.
(
2019a
).
TOM40 targets Atg2 to mitochondria-associated ER membranes for phagophore expansion
.
Cell Rep.
28
,
1744
-
1757.e5
.
Tang
,
Z.
,
Takahashi
,
Y.
and
Wang
,
H. G.
(
2019b
).
ATG2 regulation of phagophore expansion at mitochondria-associated ER membranes
.
Autophagy
15
,
2165
-
2166
.
Tanwar
,
J.
,
Saurav
,
S.
,
Basu
,
R.
,
Singh
,
J. B.
,
Priya
,
A.
,
Dutta
,
M.
,
Santhanam
,
U.
,
Joshi
,
M.
,
Madison
,
S.
,
Singh
,
A.
et al.
(
2022
).
Mitofusin-2 negatively regulates melanogenesis by modulating mitochondrial ROS generation
.
Cells
11
,
701
.
Teng
,
Y.
,
Ren
,
X.
,
Li
,
H.
,
Shull
,
A.
,
Kim
,
J.
and
Cowell
,
J. K.
(
2016
).
Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein
.
Oncogene
35
,
333
-
343
.
Theurey
,
P.
,
Tubbs
,
E.
,
Vial
,
G.
,
Jacquemetton
,
J.
,
Bendridi
,
N.
,
Chauvin
,
M. A.
,
Alam
,
M. R.
,
Le Romancer
,
M.
,
Vidal
,
H.
and
Rieusset
,
J.
(
2016
).
Mitochondria-associated endoplasmic reticulum membranes allow adaptation of mitochondrial metabolism to glucose availability in the liver
.
J. Mol. Cell Biol.
8
,
129
-
143
.
Thoudam
,
T.
,
Ha
,
C. M.
,
Leem
,
J.
,
Chanda
,
D.
,
Park
,
J. S.
,
Kim
,
H. J.
,
Jeon
,
J. H.
,
Choi
,
Y. K.
,
Liangpunsakul
,
S.
,
Huh
,
Y. H.
et al.
(
2019
).
PDK4 augments ER-mitochondria contact to dampen skeletal muscle insulin signaling during obesity
.
Diabetes
68
,
571
-
586
.
Thoudam
,
T.
,
Chanda
,
D.
,
Lee
,
J. Y.
,
Jung
,
M. K.
,
Sinam
,
I. S.
,
Kim
,
B. G.
,
Park
,
B. Y.
,
Kwon
,
W. H.
,
Kim
,
H. J.
,
Kim
,
M.
et al.
(
2023
).
Enhanced Ca(2+)-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
.
Nat. Commun.
14
,
1703
.
Toyofuku
,
T.
,
Okamoto
,
Y.
,
Ishikawa
,
T.
,
Sasawatari
,
S.
and
Kumanogoh
,
A.
(
2020
).
LRRK2 regulates endoplasmic reticulum-mitochondrial tethering through the PERK-mediated ubiquitination pathway
.
EMBO J.
39
,
e105826
.
Valverde
,
D. P.
,
Yu
,
S.
,
Boggavarapu
,
V.
,
Kumar
,
N.
,
Lees
,
J. A.
,
Walz
,
T.
,
Reinisch
,
K. M.
and
Melia
,
T. J.
(
2019
).
ATG2 transports lipids to promote autophagosome biogenesis
.
J. Cell Biol.
218
,
1787
-
1798
.
Van Den Boomen
,
D. J. H.
,
Sienkiewicz
,
A.
,
Berlin
,
I.
,
Jongsma
,
M. L. M.
,
Van Elsland
,
D. M.
,
Luzio
,
J. P.
,
Neefjes
,
J. J. C.
and
Lehner
,
P. J.
(
2020
).
A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export
.
Nat. Commun.
11
,
5559
.
Vance
,
J. E.
(
1990
).
Phospholipid synthesis in a membrane fraction associated with mitochondria
.
J. Biol. Chem.
265
,
7248
-
7256
.
Vance
,
J. E.
(
2020
).
Inter-organelle membrane contact sites: implications for lipid metabolism
.
Biol. Direct
15
,
24
.
Verfaillie
,
T.
,
Rubio
,
N.
,
Garg
,
A. D.
,
Bultynck
,
G.
,
Rizzuto
,
R.
,
Decuypere
,
J. P.
,
Piette
,
J.
,
Linehan
,
C.
,
Gupta
,
S.
,
Samali
,
A.
et al.
(
2012
).
PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress
.
Cell Death Differ.
19
,
1880
-
1891
.
Wanders
,
R. J. A.
,
Baes
,
M.
,
Ribeiro
,
D.
,
Ferdinandusse
,
S.
and
Waterham
,
H. R.
(
2023
).
The physiological functions of human peroxisomes
.
Physiol. Rev.
103
,
957
-
1024
.
Wang
,
H.
,
Sreenivasan
,
U.
,
Hu
,
H.
,
Saladino
,
A.
,
Polster
,
B. M.
,
Lund
,
L. M.
,
Gong
,
D. W.
,
Stanley
,
W. C.
and
Sztalryd
,
C.
(
2011a
).
Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria
.
J. Lipid Res.
52
,
2159
-
2168
.
Wang
,
X.
,
Eno
,
C. O.
,
Altman
,
B. J.
,
Zhu
,
Y.
,
Zhao
,
G.
,
Olberding
,
K. E.
,
Rathmell
,
J. C.
and
Li
,
C.
(
2011b
).
ER stress modulates cellular metabolism
.
Biochem. J.
435
,
285
-
296
.
Wang
,
C.
,
Dai
,
X.
,
Wu
,
S.
,
Xu
,
W.
,
Song
,
P.
,
Huang
,
K.
and
Zou
,
M. H.
(
2021a
).
FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis
.
Nat. Commun.
12
,
2616
.
Wang
,
J.
,
Fang
,
N.
,
Xiong
,
J.
,
Du
,
Y.
,
Cao
,
Y.
and
Ji
,
W. K.
(
2021b
).
An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions
.
Nat. Commun.
12
,
1252
.
Wang
,
Y.
,
Dahmane
,
S.
,
Ti
,
R.
,
Mai
,
X.
,
Zhu
,
L.
,
Carlson
,
L. A.
and
Stjepanovic
,
G.
(
2024
).
Structural basis for lipid transfer by the ATG2A-ATG9A complex
.
Nat. Struct. Mol. Biol.
32
,
35
-
47
.
Wilson
,
E. L.
and
Metzakopian
,
E.
(
2021
).
ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms
.
Cell Death Differ.
28
,
1804
-
1821
.
Wong
,
Y. C.
,
Ysselstein
,
D.
and
Krainc
,
D.
(
2018
).
Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis
.
Nature
554
,
382
-
386
.
Wong
,
Y. C.
,
Kim
,
S.
,
Peng
,
W.
and
Krainc
,
D.
(
2019
).
Regulation and function of mitochondria-lysosome membrane contact sites in cellular homeostasis
.
Trends Cell Biol.
29
,
500
-
513
.
Wu
,
Z.
and
Bowen
,
W. D.
(
2008
).
Role of sigma-1 receptor C-terminal segment in inositol 1,4,5-trisphosphate receptor activation: constitutive enhancement of calcium signaling in MCF-7 tumor cells
.
J. Biol. Chem.
283
,
28198
-
28215
.
Wu
,
W.
,
Li
,
W.
,
Chen
,
H.
,
Jiang
,
L.
,
Zhu
,
R.
and
Feng
,
D.
(
2016
).
FUNDC1 is a novel mitochondrial-associated-membrane (MAM) protein required for hypoxia-induced mitochondrial fission and mitophagy
.
Autophagy
12
,
1675
-
1676
.
Wu
,
S.
,
Lu
,
Q.
,
Wang
,
Q.
,
Ding
,
Y.
,
Ma
,
Z.
,
Mao
,
X.
,
Huang
,
K.
,
Xie
,
Z.
and
Zou
,
M. H.
(
2017
).
Binding of FUN14 domain containing 1 with inositol 1,4,5-trisphosphate receptor in mitochondria-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo
.
Circulation
136
,
2248
-
2266
.
Xia
,
Y.
,
Zhang
,
Y.
,
Sun
,
Y.
and
He
,
L.
(
2023
).
CCDC127 regulates lipid droplet homeostasis by enhancing mitochondria-ER contacts
.
Biochem. Biophys. Res. Commun.
683
,
149116
.
Xian
,
H.
,
Yang
,
Q.
,
Xiao
,
L.
,
Shen
,
H. M.
and
Liou
,
Y. C.
(
2019
).
STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism
.
Nat. Commun.
10
,
2059
.
Xie
,
Y.
,
Sun
,
W.
,
Han
,
A.
,
Zhou
,
X.
,
Zhang
,
S.
,
Shen
,
C.
,
Xie
,
Y.
,
Wang
,
C.
and
Xie
,
N.
(
2024
).
Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases
.
Front. Mol. Neurosci.
17
,
1527013
.
Xu
,
N.
,
Zhang
,
S. O.
,
Cole
,
R. A.
,
McKinney
,
S. A.
,
Guo
,
F.
,
Haas
,
J. T.
,
Bobba
,
S.
,
Farese
,
R. V.
, Jr
and
Mak
,
H. Y.
(
2012
).
The FATP1-DGAT2 complex facilitates lipid droplet expansion at the ER-lipid droplet interface
.
J. Cell Biol.
198
,
895
-
911
.
Xu
,
L.
,
Qiu
,
Y.
,
Wang
,
X.
,
Shang
,
W.
,
Bai
,
J.
,
Shi
,
K.
,
Liu
,
H.
,
Liu
,
J. P.
,
Wang
,
L.
and
Tong
,
C.
(
2022
).
ER-mitochondrial contact protein Miga regulates autophagy through Atg14 and Uvrag
.
Cell Rep.
41
,
111583
.
Yang
,
J.-F.
,
Xing
,
X.
,
Luo
,
L.
,
Zhou
,
X.-W.
,
Feng
,
J.-X.
,
Huang
,
K.-B.
,
Liu
,
H.
,
Jin
,
S.
,
Liu
,
Y.-N.
,
Zhang
,
S.-H.
et al.
(
2023
).
Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8(+) T cell metabolic fitness and function in tumors
.
Sci. Immunol.
8
,
eabq2424
.
Yeo
,
H. K.
,
Park
,
T. H.
,
Kim
,
H. Y.
,
Jang
,
H.
,
Lee
,
J.
,
Hwang
,
G.-S.
,
Ryu
,
S. E.
,
Park
,
S. H.
,
Song
,
H. K.
,
Ban
,
H. S.
et al.
(
2021
).
Phospholipid transfer function of PTPIP51 at mitochondria-associated ER membranes
.
EMBO Rep.
22
,
e51323
.
Yepuri
,
G.
,
Ramirez
,
L. M.
,
Theophall
,
G. G.
,
Reverdatto
,
S. V.
,
Quadri
,
N.
,
Hasan
,
S. N.
,
Bu
,
L.
,
Thiagarajan
,
D.
,
Wilson
,
R.
,
Diez
,
R. L.
et al.
(
2023
).
DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
.
Nat. Commun.
14
,
6900
.
Yi
,
M.
,
Weaver
,
D.
and
Hajnóczky
,
G.
(
2004
).
Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit
.
J. Cell Biol.
167
,
661
-
672
.
Young
,
P. A.
,
Senkal
,
C. E.
,
Suchanek
,
A. L.
,
Grevengoed
,
T. J.
,
Lin
,
D. D.
,
Zhao
,
L.
,
Crunk
,
A. E.
,
Klett
,
E. L.
,
Fullekrug
,
J.
,
Obeid
,
L. M.
et al.
(
2018
).
Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways
.
J. Biol. Chem.
293
,
16724
-
16740
.
Yu
,
W.
,
Sun
,
S.
,
Xu
,
H.
,
Li
,
C.
,
Ren
,
J.
and
Zhang
,
Y.
(
2020
).
TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury
.
Theranostics
10
,
11244
-
11263
.
Yu
,
F.
,
Courjaret
,
R.
,
Assaf
,
L.
,
Elmi
,
A.
,
Hammad
,
A.
,
Fisher
,
M.
,
Terasaki
,
M.
and
Machaca
,
K.
(
2024
).
Mitochondria-ER contact sites expand during mitosis
.
iScience
27
,
109379
.
Yue
,
M.
,
Hu
,
B.
,
Li
,
J.
,
Chen
,
R.
,
Yuan
,
Z.
,
Xiao
,
H.
,
Chang
,
H.
,
Jiu
,
Y.
,
Cai
,
K.
and
Ding
,
B.
(
2023
).
Coronaviral ORF6 protein mediates inter-organelle contacts and modulates host cell lipid flux for virus production
.
EMBO J.
42
,
e112542
.
Zampese
,
E.
,
Fasolato
,
C.
,
Kipanyula
,
M. J.
,
Bortolozzi
,
M.
,
Pozzan
,
T.
and
Pizzo
,
P.
(
2011
).
Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk
.
Proc. Natl. Acad. Sci. USA
108
,
2777
-
2782
.
Zatyka
,
M.
,
Rosenstock
,
T. R.
,
Sun
,
C.
,
Palhegyi
,
A. M.
,
Hughes
,
G. W.
,
Lara-Reyna
,
S.
,
Astuti
,
D.
,
Di Maio
,
A.
,
Sciauvaud
,
A.
,
Korsgen
,
M. E.
et al.
(
2023
).
Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome
.
Stem Cell Rep.
18
,
1090
-
1106
.
Zervopoulos
,
S. D.
,
Boukouris
,
A. E.
,
Saleme
,
B.
,
Haromy
,
A.
,
Tejay
,
S.
,
Sutendra
,
G.
and
Michelakis
,
E. D.
(
2022
).
MFN2-driven mitochondria-to-nucleus tethering allows a non-canonical nuclear entry pathway of the mitochondrial pyruvate dehydrogenase complex
.
Mol. Cell
82
,
1066
-
1077.e7
.
Zhao
,
Y. G.
,
Liu
,
N.
,
Miao
,
G.
,
Chen
,
Y.
,
Zhao
,
H.
and
Zhang
,
H.
(
2018
).
The ER contact proteins VAPA/B interact with multiple autophagy proteins to modulate autophagosome biogenesis
.
Curr. Biol.
28
,
1234
-
1245.e4
.
Zhao
,
G.
,
Jia
,
M.
,
Zhu
,
S.
,
Ren
,
H.
,
Wang
,
G.
,
Xin
,
G.
,
Sun
,
M.
,
Wang
,
X.
,
Lin
,
Q.
,
Jiang
,
Q.
et al.
(
2024
).
Mitotic ER-mitochondria contact enhances mitochondrial Ca(2+) influx to promote cell division
.
Cell Rep.
43
,
114794
.
Zhou
,
Z.
,
Torres
,
M.
,
Sha
,
H.
,
Halbrook
,
C. J.
,
Van Den Bergh
,
F.
,
Reinert
,
R. B.
,
Yamada
,
T.
,
Wang
,
S.
,
Luo
,
Y.
,
Hunter
,
A. H.
et al.
(
2020
).
Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes
.
Science
368
,
54
-
60
.
Zung
,
N.
and
Schuldiner
,
M.
(
2020
).
New horizons in mitochondrial contact site research
.
Biol. Chem.
401
,
793
-
809
.

Competing interests

The authors declare no competing or financial interests.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.