ABSTRACT

Eukaryotic cells replicate and partition their organelles between the mother cell and the daughter cell at cytokinesis. Polarized cells, notably the budding yeast Saccharomyces cerevisiae, are well suited for the study of organelle inheritance, as they facilitate an experimental dissection of organelle transport and retention processes. Much progress has been made in defining the molecular players involved in organelle partitioning in yeast. Each organelle uses a distinct set of factors – motor, anchor and adaptor proteins – that ensures its inheritance by future generations of cells. We propose that all organelles, regardless of origin or copy number, are partitioned by the same fundamental mechanism involving division and segregation. Thus, the mother cell keeps, and the daughter cell receives, their fair and equitable share of organelles. This mechanism of partitioning moreover facilitates the segregation of organelle fragments that are not functionally equivalent. In this Commentary, we describe how this principle of organelle population control affects peroxisomes and other organelles, and outline its implications for yeast life span and rejuvenation.

Introduction

One hallmark of eukaryotic cells is the presence of membrane-enclosed organelles that permit the coexistence of different chemical microenvironments, each precisely tailored for a defined set of biochemical reactions. Cells must maintain their organelles to retain the benefits of compartmentalization. As it is either impossible or energetically unfavorable to make organelles anew, cells have evolved elaborate mechanisms to control their organelle populations. With every round of cell division, organelles are duplicated and distributed between the two resultant cells. This process, termed organelle inheritance, ensures the faithful propagation of organelles to future generations of cells.

Cells of the yeast Saccharomyces cerevisiae undergo a repetitive pattern of growth and division termed budding. Cell division in S. cerevisiae is asymmetrical, with the formation of a bud that is initially much smaller than its mother. Thus, in contrast to cells that divide by median fission, yeast cells must actively deliver a portion of their organelles to the growing bud (Fig. 1). The remaining organelles are immobilized at defined structures in the mother cell. Organelle inheritance in budding yeast can therefore be divided into distinct processes of organelle transport and organelle retention. The ability to experimentally dissect a complex phenomenon into its individual components, along with ease of genetic manipulation, has made S. cerevisiae a powerful tool for the study of organelle inheritance.

Fig. 1.

Organelle transport driven by class V myosins in yeast. Most organelles in S. cerevisiae travel to the bud along actin cables with the help of a class V myosin motor. The organelles attach to Myo2p or Myo4p through organelle-specific adaptors. Myo2p forms a homodimer, whereas Myo4p acts as a multi-motor complex (Chung and Takizawa, 2010). Modified from Fagarasanu et al. (Fagarasanu et al., 2010).

Fig. 1.

Organelle transport driven by class V myosins in yeast. Most organelles in S. cerevisiae travel to the bud along actin cables with the help of a class V myosin motor. The organelles attach to Myo2p or Myo4p through organelle-specific adaptors. Myo2p forms a homodimer, whereas Myo4p acts as a multi-motor complex (Chung and Takizawa, 2010). Modified from Fagarasanu et al. (Fagarasanu et al., 2010).

The last decade has seen the discovery of a battery of factors involved in various aspects of organelle partitioning. Research now has shifted from the identification of individual components to an elucidation of how these factors work together in the cell to effect organelle partitioning. We are beginning to understand how inheritance factors coordinate their activities to maintain a stable population of a particular organelle, as well as how the cell orchestrates the partitioning of its organelle populations as a whole.

Here, we provide a synopsis of the recent advances in the field of organelle inheritance. Based on these findings, we propose that all organelles, regardless of origin or copy number, are partitioned between mother and daughter cells by the same fundamental mechanism involving the division of organelles and their subsequent segregation. We provide examples of how inheritance factors and the divisional machinery of an organelle cooperate to divvy up the organelle population and how the seemingly antagonistic processes of organelle transport and organelle retention act synergistically during organelle inheritance. Moreover, we outline how this mechanism of organelle population control affects other cellular processes, such as aging and rejuvenation.

Moving out – organelle transport processes

The bud-directed movement of organelles in S. cerevisiae is powered by molecular motors moving along cytoskeletal tracks. At the beginning of each cell cycle, formins assemble at the site of future bud emergence and catalyze the incorporation of actin monomers into filaments (Evangelista et al., 2002; Pruyne et al., 2002; Sagot et al., 2002). The actin cables thus formed converge at the bud neck region of the cell and radiate back into the mother cell. These cables form the tracks along which most organelles travel for their inheritance (Fig. 1).

The actin-based movement of organelles is catalyzed by the class V myosins, Myo2p and Myo4p. These molecular motors contain N-terminal domains that are required for binding to F-actin and generating force through the hydrolysis of ATP, while their C-termini form globular tails that attach to cargoes by binding to organelle-specific adaptor molecules (Sellers and Veigel, 2006). Myo4p and Myo2p divide the labor of organelle transport unevenly, as Myo4p moves only cortical endoplasmic reticulum (cER) (Estrada et al., 2003), whereas Myo2p powers the movement of secretory vesicles, Golgi, mitochondria, peroxisomes and vacuoles (Fagarasanu et al., 2010). Lipid droplets also segregate to buds in a Myo2p-dependent manner (Knoblach and Rachubinski, 2014).

The identities of many of the receptors connecting the different organelles to the cargo-binding domains of the myosin V motors have now been determined. She3p and She2p are required to attach cER elements and certain mRNAs to Myo4p, which results in the bud-specific expression of these transcripts (Estrada et al., 2003; Schmid et al., 2006; Shepard et al., 2003). Peroxisomes attach to Myo2p through inheritance of peroxisomes protein 2 (Inp2p), a peroxisomal integral membrane protein (Fagarasanu et al., 2006). Myo2p also moves a portion of the vacuole from mother cell to bud by interacting with the Vac17p–Vac8p complex (Ishikawa et al., 2003; Tang et al., 2003). The binding of Myo2p to Mmr1p and the Rab GTPase Ypt11p plays a role in the segregation of mitochondria (Frederick et al., 2008; Itoh et al., 2002; 2004). Both proteins bind Myo2p directly and have been implicated in mitochondrial inheritance, as small buds of mmr1Δ and ypt11Δ cells lack mitochondria (Frederick et al., 2008; Itoh et al., 2004). However, the localization of Ypt11p to the ER (Buvelot Frei et al., 2006) and late Golgi vesicles (Arai et al., 2008) raises the question as to whether Ypt11p attaches mitochondria directly to Myo2p or moves ER elements to which mitochondria adhere (see also Box 1). Adaptor proteins that attach Myo2p to secretory vesicles include the Rab GTPases Ypt31p, its paralog Ypt32p and Sec4p, as well as the exocyst component Sec15p, which mediates the polarized delivery of transport vesicles to the plasma membrane (Jin et al., 2011; Lipatova et al., 2008; Santiago-Tirado et al., 2011). Myo2p also carries the plus ends of cytoplasmic microtubules to the bud through interaction with the Kar9p–Bim1p complex (Beach et al., 2000; Yin et al., 2000) and thus orients the nucleus prior to mitosis. Of note, the nucleus itself, along with the perinuclear ER, is segregated to the bud by microtubules (Du et al., 2001; Huffaker et al., 1988; Jacobs et al., 1988) (Fig. 1).

In vivo time-lapse microscopy of organelle dynamics has revealed that multi-copy organelles such as peroxisomes are transferred from mother cell to bud in a highly ordered vectorial process (Fagarasanu et al., 2006; Hoepfner et al., 2001; Rossanese et al., 2001). Moreover, Myo2p moves different cargoes at distinct times in the cell cycle (Eves et al., 2012); for example, movement of peroxisomes always precedes movement of mitochondria (Knoblach et al., 2013). How does the cell coordinate organelle movement so as not to impair organelle function or impede cell cycle progression? Stringent control mechanisms have been identified at the level of both the myosin V motor and the organelle adapters.

Our understanding of how Myo2p associates with cargo was advanced significantly by the determination of the crystal structure of the Myo2p tail (Pashkova et al., 2006). Mutagenesis of conserved surface amino acids in the tail identified patches required for its binding specifically to vacuoles, mitochondria, secretory vesicles and peroxisomes (Altmann et al., 2008; Catlett et al., 2000; Catlett and Weisman, 1998; Fagarasanu et al., 2009; Pashkova et al., 2006). Confirmation that these patches represent bona fide binding sites for organelles was obtained by demonstrating that they are the sites at which the corresponding organelle-specific adaptors bind to Myo2p (Fagarasanu et al., 2009; Ishikawa et al., 2003; Lipatova et al., 2008). Later work showed that binding of eight of the nine known Myo2p cargo adaptors overlaps at one of two distinct Myo2p surface patches (Eves et al., 2012). This finding has challenged the concept that Myo2p acts as a scaffold that simultaneously exposes sites for attachment to its different cargoes; rather it suggests that different types of organelles compete for access to Myo2p by steric exclusion of other organelles and that the availability of Myo2p adaptors on the surface of organelles has to be tightly regulated to dictate the precise timing of Myo2p recruitment and organelle motility (Fagarasanu et al., 2009).

Inp2p and Vac17p are extensively studied Myo2p adaptors that form transport complexes with peroxisomes and vacuoles, respectively. Both proteins have structural and regulatory elements in common. Coiled-coil domains are in part overlapping with the Myo2p-binding domains of Vac17p and Inp2p, whereas conserved phosphorylation sites and a PEST motif identify the proteins as targets for post-translational modification and rapid proteolytic turnover (Fig. 2). Inp2p and Vac17p fluctuate in level with the cell cycle; they reach maximum levels during peroxisome and vacuole inheritance and are degraded after their organelles have been delivered to the bud (Fagarasanu et al., 2006; Peng and Weisman, 2008). Inp2p and Vac17p each contain several recognition sites for the cyclin-dependent kinase Cdk1p and are phosphorylated during the cell cycle (Fagarasanu et al., 2009; Peng and Weisman, 2008). Direct phosphorylation of Vac17p by Cdk1p has been implicated in the increased affinity of Vac17p for Myo2p (Peng and Weisman, 2008). The p21-activated kinases (PAKs) Cla4p and Ste20p have been implicated in terminating vacuole inheritance (Bartholomew and Hardy, 2009), but whether phosphorylation of Vac17p is required for its degradation and whether Vac17p is a direct target of PAKs remained unclear. A recent study has shown that different stages of vacuole inheritance are controlled by distinct Vac17p phosphorylation events. Phosphorylation of Vac17p at several Cdk1p sites leads to recruitment of Myo2p and the start of vacuole transport. By contrast, phosphorylation of Vac17p at a threonine residue located in its PEST motif leads to the recruitment of a ubiquitin ligase, proteasomal degradation of Vac17p, and termination of vacuole transport. It is noteworthy that the ubiquitin ligase is recruited to the transport complex only after the vacuole has entered the bud (Yau et al., 2014).

Fig. 2.

Domain organization of Inp2p and Vac17p. Inp2p and Vac17p are the peroxisomal and vacuolar organelle adaptors for Myo2p, respectively. They share coiled-coil (CC) (http://embnet.vital-it.ch/software/COILS_form.html) and PEST motifs (http://emboss.bioinformatics.nl/cgi-bin/emboss/epestfind). The coiled-coil regions of Inp2p have been found to be required for its binding to Myo2p (Fagarasanu et al., 2006), whereas the Myo2p-binding region of Vac17p overlaps only partially with its first coiled-coil domain (Ishikawa et al., 2003). Both proteins have also been found to be phosphorylated and degraded at the end of the cell cycle. Inp2p is integral to the peroxisomal membrane, whereas Vac17p docks to the vacuole through binding to Vac8p (Weisman, 2006).

Fig. 2.

Domain organization of Inp2p and Vac17p. Inp2p and Vac17p are the peroxisomal and vacuolar organelle adaptors for Myo2p, respectively. They share coiled-coil (CC) (http://embnet.vital-it.ch/software/COILS_form.html) and PEST motifs (http://emboss.bioinformatics.nl/cgi-bin/emboss/epestfind). The coiled-coil regions of Inp2p have been found to be required for its binding to Myo2p (Fagarasanu et al., 2006), whereas the Myo2p-binding region of Vac17p overlaps only partially with its first coiled-coil domain (Ishikawa et al., 2003). Both proteins have also been found to be phosphorylated and degraded at the end of the cell cycle. Inp2p is integral to the peroxisomal membrane, whereas Vac17p docks to the vacuole through binding to Vac8p (Weisman, 2006).

The signaling cascade described above exemplifies how the cell integrates spatiotemporal cues to finely tune organelle movement. Analysis of Myo2p mutants defective in binding Inp2p, and thus impaired in delivering peroxisomes to the bud, has provided another example of how class-V-myosin-driven organelle partitioning is regulated. Peroxisome inheritance is effectively uncoupled from the cell cycle in these mutants; the levels of Inp2p are increased, implying that the amount of Inp2p is not controlled by the cell cycle but rather by the distribution of peroxisomes in the cell, that is, by organelle-positioning-specific cues. The timing of Inp2p phosphorylation, by contrast, remains unaffected, and thus appears to be coupled to cell cycle progression. The increase in Inp2p abundance furthermore hints at the existence of a compensatory mechanism as the cell supplies more of the peroxisome-specific transport adaptor when peroxisome delivery to the bud is compromised (Fagarasanu et al., 2009). Indeed, organelle delivery between mother and daughter cells is apparently intricately choreographed.

In the next section we discuss mechanisms for organelle retention, which is needed for the equitable distribution of organelles between mother and daughter cells at cytokinesis.

Holding on – organelle retention processes

Budding S. cerevisiae cells retain a portion of their organelles in the mother cell, that is, they never lose the entire population of one organelle to the bud. Organelle retention is accomplished by immobilizing organelles at distinct cell structures. Some organelles, such as mitochondria and peroxisomes, are anchored at the cell periphery (Fagarasanu et al., 2005; Klecker et al., 2013; Kornmann et al., 2009; Lackner et al., 2013; Yaffe, 1999), whereas others, specifically lipid droplets, cluster around the nuclear envelope (Adeyo et al., 2011; Jacquier et al., 2011; Knoblach and Rachubinski, 2014; Wolinski et al., 2011). Organelle retention is not confined to the mother cell but also occurs in the bud to prevent the backtracking of newly inherited organelles to the mother cell (Boldogh et al., 2004; Fehrenbacher et al., 2004). Processes for organelle retention have long been proposed (Fagarasanu et al., 2005; Yang et al., 1999), yet only lately have their molecular mechanisms been elucidated. Organelles are retained in the cell by the formation of membrane contact sites, or tethers, with other organelles. Membrane contact sites not only guarantee that an organelle population is maintained over generations of cells but also define the architecture and spatial distribution of organelles and facilitate inter-organelle communication. Examples of tethers that might not affect organelle segregation directly include the mitochondrial contact site and cristae organizing system (MICOS) located in the inner mitochondrial membrane (for a review, see Pfanner et al., 2014), membrane contacts between the vacuole and mitochondria that serve to mediate lipid exchange (Elbaz-Alon et al., 2014; Hönscher et al., 2014), and membrane contacts between the ER and mitochondria involved in lipid synthesis, Ca2+ signaling and mitochondrial remodeling (for a review, see Rowland and Voeltz, 2012). We will discuss organelle tethers as they pertain to organelle dynamics and inheritance; their roles in signaling, lipid trafficking and metabolism have been reviewed elsewhere (Klecker et al., 2014; Prinz, 2014; Stefan et al., 2013).

Organelle tethers assemble at discrete foci where membranes from two organelles come into close contact but do not fuse. Specific proteins enriched at the membrane contact sites, either alone or in complex, form the tether by binding to both membranes. Tethering proteins are either integral to the membrane of one of the compartments or can be classified as membrane-associated ‘hinge’ proteins that link the integral membrane proteins to each other. Tethers that connect peroxisomes (Knoblach et al., 2013) and mitochondria (Kornmann et al., 2009) to the cER, as well as those that connect mitochondria (Klecker et al., 2013; Lackner et al., 2013) and the cER to the plasma membrane (Manford et al., 2012), have recently been resolved. As the molecular architectures of tethers have become better defined, features common to all tethers have begun to emerge. First, tethers are often made between the ER and a second organelle. Second, some organelles are maintained by more than one tether or are found to tether to more than one organelle. Third, tethers do not simply anchor organelles but actively regulate organelle dynamics.

We recently described a tether that connects peroxisomes to the cER in yeast. The tether is comprised of two proteins, Inp1p and the peroxisome biogenic protein Pex3p (Knoblach et al., 2013). Cells lacking Inp1p contain only mobile peroxisomes that are eventually driven to the bud by the Inp2p–Myo2p transport complex, whereas cells overproducing Inp1p maintain all of their peroxisomes in fixed cortical positions in the mother cell and do not transfer any peroxisomes to the daughter cell (Fagarasanu et al., 2005). Inp1p not only decorates peroxisomes but also has an affinity for a structure lining the cell cortex. Thus, Inp1p was concluded to be required for attaching peroxisomes to a then uncharacterized cortical anchor (Fagarasanu et al., 2005). The identification of mutants of Pex3p that are unable to recruit Inp1p to the peroxisomal membrane and exhibit the same phenotype as that of inp1Δ cells (Munck et al., 2009) indicated that there is a direct interaction between Pex3p and Inp1p. Pex3p is essential for peroxisome biogenesis and is integral to both the ER and the peroxisomal membranes (Hoepfner et al., 2005; Thoms et al., 2012). We showed that Inp1p contains at least two binding sites for Pex3p and acts as a molecular hinge by bridging ER-bound Pex3p and peroxisomal Pex3p into an ER–peroxisome tethering complex (Knoblach et al., 2013) (Fig. 3).

Fig. 3.

Molecular architecture of organelle tethers. Organelles ‘anchor’ in the cell by attaching to other organelles at sites of membrane contact, which contain distinct tethering proteins. (A) Peroxisomes attach to the cER by an Inp1p-mediated linkage of ER-bound Pex3p and peroxisomal Pex3p (Knoblach et al., 2013). (B) The cER tethers to the plasma membrane (PM) through three conserved protein families: the tricalbins (Tcbs), VAP family members and Ist2p (Manford et al., 2012). The tricalbins contain C2 domains that display Ca2+-stimulated lipid-binding activity and a SMP domain that is sufficient for lipid binding and ER targeting. Ist2p contains a C-terminal polybasic (PB) domain that is proposed to bind phosphatidylinositol phosphate (PIP) at the plasma membrane (Stefan et al., 2013). (C) Mitochondria use the ERMES to attach to the cER (Kornmann et al., 2009). ERMES is comprised of the glycosylated ER transmembrane protein Mmm1p, the outer mitochondrial membrane (OMM) proteins Mdm10p and Mdm34p, and the soluble protein Mdm12p. (D) Mitochondria also attach to the plasma membrane through a tethering complex consisting of Num1p, which binds the plasma membrane through its C-terminal pleckstrin homology (PH) domain and the soluble adaptor protein Mdm36p. The receptor for Mdm36p in the mitochondrial outer membrane is currently unidentified (Klecker et al., 2014; Lackner et al., 2013).

Fig. 3.

Molecular architecture of organelle tethers. Organelles ‘anchor’ in the cell by attaching to other organelles at sites of membrane contact, which contain distinct tethering proteins. (A) Peroxisomes attach to the cER by an Inp1p-mediated linkage of ER-bound Pex3p and peroxisomal Pex3p (Knoblach et al., 2013). (B) The cER tethers to the plasma membrane (PM) through three conserved protein families: the tricalbins (Tcbs), VAP family members and Ist2p (Manford et al., 2012). The tricalbins contain C2 domains that display Ca2+-stimulated lipid-binding activity and a SMP domain that is sufficient for lipid binding and ER targeting. Ist2p contains a C-terminal polybasic (PB) domain that is proposed to bind phosphatidylinositol phosphate (PIP) at the plasma membrane (Stefan et al., 2013). (C) Mitochondria use the ERMES to attach to the cER (Kornmann et al., 2009). ERMES is comprised of the glycosylated ER transmembrane protein Mmm1p, the outer mitochondrial membrane (OMM) proteins Mdm10p and Mdm34p, and the soluble protein Mdm12p. (D) Mitochondria also attach to the plasma membrane through a tethering complex consisting of Num1p, which binds the plasma membrane through its C-terminal pleckstrin homology (PH) domain and the soluble adaptor protein Mdm36p. The receptor for Mdm36p in the mitochondrial outer membrane is currently unidentified (Klecker et al., 2014; Lackner et al., 2013).

Mitochondrial distribution and partitioning are regulated by several pathways. The ER–mitochondria encounter structure (ERMES) is one of at least two mitochondrial tethers acting at the cortex in the mother cell. ERMES links mitochondria to the cER and is formed by a complex made up of both ER and mitochondrial proteins. Maintenance of mitochondrial morphology protein 1 (Mmm1p), formerly believed to be a bona fide mitochondrial protein, is actually an ER-resident integral membrane protein (Kornmann et al., 2009) that bridges mitochondria to the ER by binding to a protein complex in the mitochondrial outer membrane (Fig. 3). Members of the protein complex share a synaptotagmin-like mitochondrial lipid-binding protein domain that is important for their localization at the ER-mitochondrion junction (Toulmay and Prinz, 2012). Cells lacking ERMES contain enlarged spherical mitochondria, frequently lack mitochondria in the bud and exhibit growth deficits on non-fermentable carbon sources. This phenotype can be rescued by the expression of an artificial mitochondrion–ER tether (Kornmann et al., 2009).

Mitochondrion–plasma-membrane contacts are mediated by a complex containing nuclear migration protein 1 (Num1p), which binds to the plasma membrane through its C-terminal pleckstrin homology domain, and mitochondrial distribution and morphology protein 36 (Mdm36p), a peripheral membrane protein of mitochondria that is thought to connect Num1p to a yet unidentified receptor in the outer mitochondrial membrane (Klecker et al., 2013; Lackner et al., 2013) (Fig. 3). Num1p provides a cortical attachment for microtubules during positioning of the mitotic spindle (Heil-Chapdelaine et al., 2000), but surprisingly num1Δ mutants also show defects in mitochondrial distribution (Cerveny et al., 2007). Mitochondria are normally anchored to the cell cortex, but this peripheral localization is lost in cells lacking Num1p. The Num1p tether promotes mitochondrial retention in the mother cell, as deletion of the NUM1 gene leads to the formation of mother cells without mitochondria (Cerveny et al., 2007; Klecker et al., 2013; Lackner et al., 2013). The mitochondrial distribution and morphology defects observed in num1Δ cells can be corrected by expression of an artificial mitochondrion–plasma-membrane tether, which demonstrates the importance of Num1p in the cortical anchoring of mitochondria (Klecker et al., 2013; Lackner et al., 2013).

Anchorage of mitochondria in buds requires two factors, Mmr1p and Ypt11p (Frederick et al., 2008; Itoh et al., 2002; Itoh et al., 2004). Mmr1p, a member of the DSL1 family of tethering proteins, has been reported to link mitochondria with the cER (Swayne et al., 2011). Super-resolution microscopy has revealed that Mmr1p enriches at punctate structures on opposing surfaces of mitochondria and ER sheets underlying the bud tip. Deletion of Mmr1p does not affect the normal dynamics of mitochondria or the distribution of the cER but impairs anchoring of mitochondria at the bud tips (Swayne et al., 2011). Of note, although the cER and mitochondria are moved to the bud by two independent motors (Estrada et al., 2003), a defect in ER inheritance has also been shown to impair mitochondrial inheritance. Ypt11p is a Rab-like protein that localizes to the cER (Buvelot Frei et al., 2006) and also interacts with Myo2p (Arai et al., 2008; Itoh et al., 2004). Deletion of YPT11 not only prevents the accumulation of cER at the bud tip (Buvelot Frei et al., 2006) but also inhibits the anchoring of mitochondria at the bud tip (Itoh et al., 2002; Swayne et al., 2011).

Some proteins involved in anchoring and partitioning mitochondria have been ascribed multiple and sometimes contradictory functions (Westermann, 2014) (Box 1). Mmr1p and Num1p act antagonistically, as the distribution of mitochondria is shifted to the mother cell in mmr1Δ cells (Itoh et al., 2004; Swayne et al., 2011) but to the bud in num1Δ cells (Klecker et al., 2013; Lackner et al., 2013). Not surprisingly, deletion of both MMR1 and NUM1 alleviates the phenotype observed in cells deleted for one of the genes (Hoppins et al., 2011). In a num1Δ mmr1Δ double mutant, equidistribution of mitochondria between the mother cell and the bud is partially restored (Klecker et al., 2013) because mitochondria can move freely in both directions without the constraint of cortical anchors (Klecker et al., 2014). Mmr1p and Ypt11p, by contrast, have similar functions, as overexpression of YPT11 compensates for loss of MMR1 (Swayne et al., 2011). Inheritance of mitochondria by the bud is blocked in a mmr1Δ ypt11Δ double mutant, which additionally suggests that these proteins have redundant functions (Chernyakov et al., 2013). Notably, the defect in mitochondrial inheritance can be rescued by expression of the chimeric mitochondrion-specific motor Myo2p–Fis1p, which carries a mitochondrial outer membrane anchor in place of the cargo-binding domain of Myo2p (Förtsch et al., 2011).

The junction between the ER and the plasma membrane is comprised of six ER-resident proteins, which all need to be eliminated to reduce the normally extensive interactions between the ER and the plasma membrane (Manford et al., 2012). This suggests that these six proteins mediate ER–plasma-membrane tethering independently of one another. Three conserved protein families are involved in contact formation: the synaptotagmin-like tricalbins, VAP family members and Ist2p (Toulmay and Prinz, 2012; Wolf et al., 2012). Four of the six proteins are integral to the ER membrane and have conserved cytosolic lipid-binding domains (Fig. 3). ER–plasma-membrane tethering is thus likely mediated through a protein–lipid, rather than protein–protein, interaction (Stefan et al., 2013).

Loss of ER–plasma-membrane tethering results in a separation of the cER from the plasma membrane, repositioning of the cER to the cell interior, elevated levels of phosphoinositides at the plasma membrane and a constitutive activation of the unfolded protein response (Manford et al., 2012). How this collapse of the cER affects the intracellular distribution of other organelles, such as peroxisomes and mitochondria, that normally attach to it has not been investigated.

Organelle division – integrating transport and retention

Organelle transport and retention have long been considered to be mutually exclusive and antagonistic processes that need to play a ‘tug of war’ to achieve an equidistribution of organelles between mother cell and bud (Fagarasanu et al., 2007). This notion is derived in part from the observation that transport and retention factors have inverse concentration gradients across the cell division axis and thus appear to be preferentially associated with a subset of organelles. Inp2p can be detected only on bud-localized peroxisomes in wild-type cells (Fagarasanu et al., 2006), whereas Inp1p is confined to mother cell peroxisomes (Knoblach et al., 2013). These observations do not explain how individual peroxisomes are chosen to acquire one inheritance factor over the other, how the cell rebalances its peroxisome population after the Inp1p- and Inp2p-containing peroxisomes have met different segregation fates, and how the cell ‘counts’ its peroxisomes so as not to lose control of its peroxisome population as a whole (Knoblach and Rachubinski, 2013).

Tracking the movement of individual peroxisomes by photoconversion of a fluorescently tagged peroxisomal matrix protein has revealed that peroxisomes in the mother cell are not fully released from their cortical tethers, whereas peroxisomes that travel to the bud contain photoconverted reporter and must therefore be the product of a division event in the mother cell (Knoblach et al., 2013). Mutants defective in peroxisome division contain a single giant peroxisome (Hoepfner et al., 2001; Kuravi et al., 2006). Inp1p and Inp2p are present on this enlarged peroxisome but are polarized to opposite ends. Inp2p is enriched on the part of the peroxisome that protrudes into the bud, whereas Inp1p is found on the part that is retained in the mother cell (Fig. 4). The concentration gradient of Inp1p can be explained by the geometry of the ER–peroxisome tether. Inp1p attaches to the ER membrane before it connects with the peroxisomal surface; it is therefore confined to the part of the peroxisome that is in direct contact with the ER (Knoblach et al., 2013). The Inp2p concentration gradient is likely established by Myo2p, which attaches to the peroxisomal membrane through Inp2p and exerts an anterograde pulling force, thereby concentrating Inp2p at the tip of the peroxisomal tubule. Of note, the giant peroxisome is split apart late in the cell cycle as it is overextended by Inp2p–Myo2p-dependent pulling forces on one side and by Pex3p–Inp1p-dependent retention forces on the other side. Thus, the mother cell keeps a peroxisome fragment containing Inp1p, whereas the daughter cell receives a peroxisome fragment containing Inp2p (Fig. 4). A gradient of inheritance factors similar to the one observed in wild-type cells is thus established in the peroxisome divisional mutants. We contend that every peroxisome replicates and splits between mother cell and bud, thus ensuring that the mother cell keeps, and the daughter cell receives, their fair and equitable allotment of peroxisomes (Knoblach and Rachubinski, 2013).

Fig. 4.

ER-mediated segregation of peroxisomes and mitochondria. Peroxisomes and mitochondria might use similar mechanisms for their ER-mediated segregation. (A) Mitochondria are tethered to the cER by ERMES. The ER encircles mitochondria (in red) at sites where future division will occur. The dynamin-related protein Dnm1p is recruited to the surface of mitochondria, where it multimerizes and causes mitochondrial fission. After fission has occurred, the ER remains associated with the mitochondrial fragment that retains the ERMES complex. The other mitochondrial fragment containing the Myo2p adaptor Mmr1p is transported to the bud. (B) Peroxisomes (in green) are tethered to the cER by Inp1p, which also interacts with the dynamin-related protein Vps1p. Inp2p mediates the attachment of peroxisomes to Myo2p, which exerts a bud-directed pulling force. After fission, the ER remains associated with the peroxisomal fragment that contains Inp1p, whereas the peroxisomal fragment containing Inp2p is transported to the bud. It is unknown whether the ER encircles peroxisomes prior to their division (‘?’). (C) Asymmetric segregation of Inp1p and Inp2p on peroxisomes. Yeast cells expressing the peroxisomal reporter mCherry–PTS1 and the GFP-tagged inheritance factors Inp1p and Inp2p, are depicted in the top and middle panels. These cells lack the dynamin-related GTPases Vps1p and Dnm1p and therefore contain only one enlarged peroxisome. This peroxisome splits apart late during bud growth. Inp1p is retained in the mother cell, whereas Inp2p segregates to the bud (bottom panel). Scale bar: 1 µm. Modified from Knoblach et al. (Knoblach et al., 2013).

Fig. 4.

ER-mediated segregation of peroxisomes and mitochondria. Peroxisomes and mitochondria might use similar mechanisms for their ER-mediated segregation. (A) Mitochondria are tethered to the cER by ERMES. The ER encircles mitochondria (in red) at sites where future division will occur. The dynamin-related protein Dnm1p is recruited to the surface of mitochondria, where it multimerizes and causes mitochondrial fission. After fission has occurred, the ER remains associated with the mitochondrial fragment that retains the ERMES complex. The other mitochondrial fragment containing the Myo2p adaptor Mmr1p is transported to the bud. (B) Peroxisomes (in green) are tethered to the cER by Inp1p, which also interacts with the dynamin-related protein Vps1p. Inp2p mediates the attachment of peroxisomes to Myo2p, which exerts a bud-directed pulling force. After fission, the ER remains associated with the peroxisomal fragment that contains Inp1p, whereas the peroxisomal fragment containing Inp2p is transported to the bud. It is unknown whether the ER encircles peroxisomes prior to their division (‘?’). (C) Asymmetric segregation of Inp1p and Inp2p on peroxisomes. Yeast cells expressing the peroxisomal reporter mCherry–PTS1 and the GFP-tagged inheritance factors Inp1p and Inp2p, are depicted in the top and middle panels. These cells lack the dynamin-related GTPases Vps1p and Dnm1p and therefore contain only one enlarged peroxisome. This peroxisome splits apart late during bud growth. Inp1p is retained in the mother cell, whereas Inp2p segregates to the bud (bottom panel). Scale bar: 1 µm. Modified from Knoblach et al. (Knoblach et al., 2013).

If organelle division is obligatory for organelle inheritance, how are these processes coordinated? Peroxisomes and mitochondria are known to share components of their divisional machineries (Delille et al., 2009). New evidence suggests that peroxisomes and mitochondria also have a common mechanism of distributing themselves between mother cell and bud, which is controlled by their tethering to the ER (Fig. 4).

Inp1p, the hinge protein that anchors peroxisomes to the cER by forming a bridge between ER-bound Pex3p and peroxisomal Pex3p, has been ascribed a second function in controlling peroxisome size and number. Cells lacking Inp1p have fewer and larger peroxisomes than wild-type cells, and cells overexpressing Inp1p contain numerous small peroxisomes. These findings suggest that there is a role for Inp1p in peroxisome division (Fagarasanu et al., 2005). Inp1p physically interacts with Pex25p, Pex30p and Vps1p (Fagarasanu et al., 2005), proteins that modulate the elongation and scission steps of peroxisome division (Schrader et al., 2012). Pex25p is a member of the Pex11 family of proteins that cause tubulation of peroxisomes through membrane remodeling (Koch et al., 2010), and it has also been implicated in the de novo formation of peroxisomes at the ER (Agrawal and Subramani, 2013). Pex30p, a protein localized at the ER–peroxisome interface, regulates peroxisome size and number (David et al., 2013; Yan et al., 2008). The dynamin-related GTPase Vps1p carries out the final scission step of peroxisome division, as in its absence only large peroxisomes with a beads-on-a-string morphology are observed (Hoepfner et al., 2001). How Inp1p coordinates its dual activities in peroxisome immobilization and division is unknown, but whatever its mode of regulation, Inp1p ensures that peroxisomes are not only ‘holding on’ in the mother cell but also ‘shipping out’ to the bud.

Mitochondria form a highly dynamic tubular network, which is required for their faithful partitioning and is maintained by opposing fusion and fission events. Mutants lacking factors that are essential for mitochondrial fusion, such as Fzo1p, are unable to inherit mitochondrial DNA (Hermann et al., 1998). This defect can be rescued in part by deleting genes that are required for mitochondrial fission (Sesaki and Jensen, 1999). The dynamin-related GTPase Dnm1p is a core component of the mitochondrial divisional machinery (Bleazard et al., 1999; Mozdy et al., 2000). Dnm1p assembles into spirals on the outside of the mitochondrion and uses GTP hydrolysis to sever the mitochondrial membranes (reviewed by Friedman and Nunnari, 2014). In-vitro-reconstituted Dnm1p rings have a diameter of ∼100 nm, which is too small to encircle mitochondria, as they have a diameter of ∼300 nm (Ingerman et al., 2005). How mitochondrial fission sites are selected and whether external forces contribute to the constriction of mitochondria were unresolved questions; however, ER tubules have recently been shown to encircle mitochondria at the sites at which future division would occur (Friedman et al., 2011). The ER is connected to mitochondria at sites of fission by the ERMES. Remarkably, the ERMES subunit Mmm1p has been found in small, punctate structures close to a subset of matrix-localized mitochondrial DNA nucleoids (Hobbs et al., 2001), suggesting that at least some nucleoids are connected to the ER by a protein complex that spans both mitochondrial membranes. The nucleoids colocalizing with Mmm1p are actively replicating (Meeusen and Nunnari, 2003) and display oscillatory movements, which likely contributes to their effective segregation (Murley et al., 2013). Moreover, the ERMES remains associated with one of the two mitochondrial fragments after fission has occurred, thereby liberating the other fragment (Murley et al., 2013) (Fig. 4). It is notable that a fraction of the Dnm1p molecules forms complexes with Num1p, and num1Δ dnm1Δ double mutant cells often lack mitochondria in their mother cells and accumulate all mitochondria in their buds (Cerveny et al., 2007). Mitochondria thus seem to recapitulate a segregation strategy in which one portion of the organelle remains tethered at the cortex of the mother cell, while another portion is split off for delivery to the bud.

Recently, Myo2p has been shown to play a prominent role in organelle division in addition to its function in organelle transport. Mutants in which Myo2p can no longer attach to the peroxisomal surface do not exhibit bud-directed polarization of peroxisomes (Motley and Hettema, 2007), and peroxisomes remain associated with the same cell over many generations because they are not released from their cortical tethers (Knoblach et al., 2013). These peroxisomes then also accumulate Inp2p and cannot be severed by Myo2p and transported to the bud (Fagarasanu et al., 2009; Knoblach et al., 2013).

In the next section we will provide examples of how a replication-based system of organelle partitioning contains an intrinsic quality control mechanism that affords cells tight control over their organelle populations. The implications of this process on cell aging and rejuvenation are discussed.

Functional consequences – inequality in organelle segregation

Even when organelles divide in an apparently symmetrical manner, they can contribute to the asymmetric segregation of their components if the fragments kept by the mother cell and inherited by the daughter cell are not functionally equivalent (Fig. 5) (Ouellet and Barral, 2012). The nucleus, whose envelope remains intact during mitosis in yeast, is an extensively studied example of an asymmetrically segregated organelle.

Fig. 5.

Stochastic and replication-based models of organelle inheritance. The segregation of a multi-copy organelle with two distinct surface proteins (red, green) between mother cell and bud is depicted. In the stochastic segregation model (A), one organelle is initially transferred to the bud. Organelles later adjust their numbers by replicating. The abundance and protein compositions of mother-cell- and bud-localized organelles remain undefined. In the replication-based model (B), organelles divide prior to being partitioned. Equal numbers of organelles remain anchored in the mother cell and are transferred to the bud. The surface proteins have different segregation fates due to unequal organelle division.

Fig. 5.

Stochastic and replication-based models of organelle inheritance. The segregation of a multi-copy organelle with two distinct surface proteins (red, green) between mother cell and bud is depicted. In the stochastic segregation model (A), one organelle is initially transferred to the bud. Organelles later adjust their numbers by replicating. The abundance and protein compositions of mother-cell- and bud-localized organelles remain undefined. In the replication-based model (B), organelles divide prior to being partitioned. Equal numbers of organelles remain anchored in the mother cell and are transferred to the bud. The surface proteins have different segregation fates due to unequal organelle division.

Extra-chromosomal DNA (rDNA) circles, which pop out of the chromosome as a result of homologous recombination between adjacent copies of rDNA repeats, are thought to contribute to replicative aging by titrating cellular components as they accumulate (Sinclair et al., 1998). Consistent with this hypothesis are observations that the expression of high-copy number plasmids reduces replicative lifespan (Falcón and Aris, 2003), whereas lowering the frequency of recombination at the rDNA locus leads to lifespan extension (McCormick et al., 2014). rDNA circles are segregated unevenly between mother and daughter cells, with a retention frequency of >98% by the mother cell nucleus (Sinclair and Guarente, 1997). A diffusion barrier consisting of septins and sphingolipids in the envelope of anaphase nuclei controls the segregation of nuclear constituents (Boettcher et al., 2012; Clay et al., 2014; Shcheprova et al., 2008), but its mechanism is still controversial. One study suggests that the diffusion barrier prevents the passage of old nuclear pore complexes (NPCs) to the daughter cell nucleus and that the binding of rDNA circles to NPCs might be responsible for their retention (Shcheprova et al., 2008). Other studies report that existing NPCs can be inherited by the daughter cell nucleus (Khmelinskii et al., 2010), although NPCs that are damaged or lack essential components are retained in the mother cell (Colombi et al., 2013; Makio et al., 2013). It is noteworthy that mutations affecting the strength of the diffusion barrier in the nuclear envelope also affect the frequency of plasmid retention by the mother cell nucleus (Gehlen et al., 2011; Lindstrom et al., 2011; Shcheprova et al., 2008). Visualization of episomes confirms that they are retained in the mother cell nucleus but diffuse freely throughout the nucleoplasm (Gehlen et al., 2011). The geometry of the nucleus, as well as the short yeast division cycle, might thus contribute to the uneven segregation of rDNA circles (Ouellet and Barral, 2012).

The ER is an endomembrane system comprised of sheets and tubules that is essential for cell viability. Because of its complex geometry, it is difficult to track the inheritance of individual ER components. It has been observed that yeast cells respond to acute stress by completely inhibiting ER inheritance (Babour et al., 2010), thus producing daughter cells that are inviable. This extreme case of asymmetric organelle division ensures that only undamaged organelle material is segregated to the daughter cell, thereby avoiding imposing an immediate functional disadvantage on her. However, the ER fragments retained by the mother cell and inherited by the daughter cell are non-equivalent even under normal cell division. A diffusion barrier similar to the one found in the outer membrane of the nuclear envelope polarizes the ER into separate mother and bud domains (Chao et al., 2014; Clay et al., 2014; Luedeke et al., 2005). A septin ring at the bud neck enables the recruitment of polarization factors and sphingolipids to this site. The concerted action of these factors prevents the free diffusion of transmembrane, and potentially luminal, ER proteins between mother cell and bud (reviewed by Higuchi-Sanabria et al., 2014).

Peroxisomes and mitochondria are multi-copy organelles that regulate the size of their networks through proliferation and fission events (Rafelski et al., 2012; Schrader et al., 2011). The mitochondrial reticulum is maintained by continuous exchange of materials between individual mitochondria, and mutations in the mitochondrial fusion and fission machineries affect yeast lifespan (Scheckhuber et al., 2007; Scheckhuber et al., 2011). Most mitochondrial and peroxisomal proteins appear to be homogenously partitioned between mother and daughter cells (Menendez-Benito et al., 2013), but new findings indicate that some proteins preferentially associate with mother-cell- or bud-localized peroxisomes, respectively (Fig. 4).

Mitochondria play a central role in cellular aging and are considered to be both targets of the aging process and contributors to it (Hughes and Gottschling, 2012). Mitochondria are indirectly influenced by vacuoles and are non-equivalent in older and younger cells. Vacuoles in buds have lower pH than those in mother cells, which is due to mother cell retention of the plasma membrane ATPase Pma1p, which pumps protons from the cytosol, thus limiting the number of protons available to acidify the vacuole (Henderson et al., 2014). As vacuolar acidity declines in aging mother cells, neutral amino acids accumulate and become sequestered by mitochondria, causing mitochondrial fragmentation and loss of function (Hughes and Gottschling, 2012). Moreover, mitochondria are partitioned asymmetrically between mother and daughter cells. Only ‘healthy’ mitochondria, which contain less reactive oxygen species and are more reducing than mother cell mitochondria, are inherited by the bud (Higuchi et al., 2013; McFaline-Figueroa et al., 2011; Vevea et al., 2013). Actin dynamics and anchorage of mitochondria at the bud tip ensure that mitochondria are segregated according to their functional state (reviewed by Higuchi-Sanabria et al., 2014; Vevea et al., 2014). Actin cables undergo a continuous retrograde flow from bud to mother cell, which is caused by actin nucleation at the bud tip and pulling forces exerted by the type II myosin Myo1p at the bud neck (Huckaba et al., 2006). Consequently, mitochondria have to swim ‘upstream’ for their inheritance. Increasing the rate of retrograde actin cable flow (RACF) has been shown to increase mitochondrial fitness in buds, whereas decreasing RACF has the opposite effect (Higuchi et al., 2013). This suggests that RACF acts as a filter to prevent the inheritance of less-fit mitochondria. In addition, once mitochondria have entered the bud, they need to be arrested at the cER of the bud tip to maintain their asymmetric distribution. In mmr1Δ and ypt11Δ mutants, healthy mitochondria are not effectively segregated from less-healthy mitochondria, which leads to breakdown in the mother–daughter age asymmetry of cells (McFaline-Figueroa et al., 2011; Rafelski et al., 2012).

Replicative lifespan is defined as the number of times a cell can divide before it enters senescence. Conceptually, a bud is born ‘young’, that is, it has a full replicative lifespan even if it comes from an old mother cell. Mother–daughter age asymmetry is a consequence of asymmetric cell division. Protein aggregates containing damaged or unfolded proteins are aging determinants that are retained by the mother cell through their sequestration in quality control compartments (Kaganovich et al., 2008; Spokoini et al., 2012), but are also selectively removed from daughter cells (Hill et al., 2014; Liu et al., 2010; Song et al., 2014). Rejuvenation determinants, such as cytosolic catalase that protects cells from oxidative damage, have a higher activity in the bud than in the mother cell (Erjavec and Nyström, 2007). A replication-based means of organelle partitioning evidently contributes to, and might be a prerequisite for, the establishment of a mother–daughter age asymmetry in yeast.

Outlook

Why should organelle inheritance require the multiple levels of control described above? After all, each daughter cell need only receive some material that can be used to seed the expansion of an organelle. However, we have come far from the view that organelle inheritance is a random event and that mother and daughter cells retain and acquire their organelle populations simply by chance. Recent discoveries have led not only to the identification of many factors involved in organelle inheritance but have also afforded us a much better understanding of how these factors cooperate to ensure that organelles are equitably, though not evenly, shared between mother cell and daughter cell. As our journey continues, we expect even more exciting and surprising discoveries about how organelle inheritance enables cells to maintain the advantages afforded by compartmentalization of function.

Box 1. Open questions in the field of mitochondrial inheritance

ERMES and Num1p provide attachment of mitochondria to the cER and the plasma membrane of mother cells (blue spheres). These tethers are non-equivalent, as only the loss of Num1p leads to defects in mitochondrial retention (Cerveny et al., 2007; Klecker et al., 2013; Lackner et al., 2013). Two models have been proposed for mitochondrion–plasma-membrane tethering. In the first model, Num1p links mitochondria directly to the plasma membrane (Klecker et al., 2013), whereas the second model suggests a participation of the cER in the formation of a mitochondrion–ER–plasma-membrane tether (Lackner et al., 2013). It is thus currently unknown how many membranes participate in Num1p-mediated mitochondrial tethering in the mother cell (‘?’ in figure). Active segregation of mitochondria and their tethering at the bud tip depend on Mmr1p and Ypt11p (Chernyakov et al., 2013). Both proteins have been ascribed multiple functions. Mmr1p has been identified as the mitochondrion-specific transport adaptor for Myo2p (Itoh et al., 2004) and as a tether that connects mitochondria to the cER at the bud tip (Swayne et al., 2011) (brown sphere). Bud-specific expression of the MMR1 transcript (Shepard et al., 2003) makes it questionable whether Mmr1p can act in directed movement of mitochondria from mother cell to bud. Conversely, if the primary function of Mmr1p is to act as a tether, it would be worthwhile to identify its binding partner(s) at the ER membrane (‘?’ in figure). Ypt11p has been identified as an adaptor protein that connects late Golgi cisternae to Myo2p through its interaction with the coatomer subunit Ret2p (Arai et al., 2008), as an adaptor for Myo2p on mitochondria (Itoh et al., 2002), as required for the retention of newly inherited mitochondria at the bud tip (Boldogh et al., 2004) and as a docking protein for cER at the bud tip (Buvelot Frei et al., 2006). Ypt11p is a Rab GTPase that is regulated by phosphorylation and degradation (Lewandowska et al., 2013).

graphic

Funding

This work was supported by the Canadian Institutes of Health Research [grant number 9208 to R.A.R.].

References

Adeyo
O.
,
Horn
P. J.
,
Lee
S.
,
Binns
D. D.
,
Chandrahas
A.
,
Chapman
K. D.
,
Goodman
J. M.
(
2011
).
The yeast lipin orthologue Pah1p is important for biogenesis of lipid droplets.
J. Cell Biol.
192
,
1043
1055
.
Agrawal
G.
,
Subramani
S.
(
2013
).
Emerging role of the endoplasmic reticulum in peroxisome biogenesis.
Front. Physiol.
4
,
286
.
Altmann
K.
,
Frank
M.
,
Neumann
D.
,
Jakobs
S.
,
Westermann
B.
(
2008
).
The class V myosin motor protein, Myo2, plays a major role in mitochondrial motility in Saccharomyces cerevisiae.
J. Cell Biol.
181
,
119
130
.
Arai
S.
,
Noda
Y.
,
Kainuma
S.
,
Wada
I.
,
Yoda
K.
(
2008
).
Ypt11 functions in bud-directed transport of the Golgi by linking Myo2 to the coatomer subunit Ret2.
Curr. Biol.
18
,
987
991
.
Babour
A.
,
Bicknell
A. A.
,
Tourtellotte
J.
,
Niwa
M.
(
2010
).
A surveillance pathway monitors the fitness of the endoplasmic reticulum to control its inheritance.
Cell
142
,
256
269
.
Bartholomew
C. R.
,
Hardy
C. F.
(
2009
).
p21-activated kinases Cla4 and Ste20 regulate vacuole inheritance in Saccharomyces cerevisiae.
Eukaryot. Cell
8
,
560
572
.
Beach
D. L.
,
Thibodeaux
J.
,
Maddox
P.
,
Yeh
E.
,
Bloom
K.
(
2000
).
The role of the proteins Kar9 and Myo2 in orienting the mitotic spindle of budding yeast.
Curr. Biol.
10
,
1497
1506
.
Bleazard
W.
,
McCaffery
J. M.
,
King
E. J.
,
Bale
S.
,
Mozdy
A.
,
Tieu
Q.
,
Nunnari
J.
,
Shaw
J. M.
(
1999
).
The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast.
Nat. Cell Biol.
1
,
298
304
.
Boettcher
B.
,
Marquez-Lago
T. T.
,
Bayer
M.
,
Weiss
E. L.
,
Barral
Y.
(
2012
).
Nuclear envelope morphology constrains diffusion and promotes asymmetric protein segregation in closed mitosis.
J. Cell Biol.
197
,
921
937
.
Boldogh
I. R.
,
Ramcharan
S. L.
,
Yang
H. C.
,
Pon
L. A.
(
2004
).
A type V myosin (Myo2p) and a Rab-like G-protein (Ypt11p) are required for retention of newly inherited mitochondria in yeast cells during cell division.
Mol. Biol. Cell
15
,
3994
4002
.
Buvelot Frei
S.
,
Rahl
P. B.
,
Nussbaum
M.
,
Briggs
B. J.
,
Calero
M.
,
Janeczko
S.
,
Regan
A. D.
,
Chen
C. Z.
,
Barral
Y.
,
Whittaker
G. R.
et al. (
2006
).
Bioinformatic and comparative localization of Rab proteins reveals functional insights into the uncharacterized GTPases Ypt10p and Ypt11p.
Mol. Cell. Biol.
26
,
7299
7317
.
Catlett
N. L.
,
Weisman
L. S.
(
1998
).
The terminal tail region of a yeast myosin-V mediates its attachment to vacuole membranes and sites of polarized growth.
Proc. Natl. Acad. Sci. USA
95
,
14799
14804
.
Catlett
N. L.
,
Duex
J. E.
,
Tang
F.
,
Weisman
L. S.
(
2000
).
Two distinct regions in a yeast myosin-V tail domain are required for the movement of different cargoes.
J. Cell Biol.
150
,
513
526
.
Cerveny
K. L.
,
Studer
S. L.
,
Jensen
R. E.
,
Sesaki
H.
(
2007
).
Yeast mitochondrial division and distribution require the cortical num1 protein.
Dev. Cell
12
,
363
375
.
Chao
J. T.
,
Wong
A. K.
,
Tavassoli
S.
,
Young
B. P.
,
Chruscicki
A.
,
Fang
N. N.
,
Howe
L. J.
,
Mayor
T.
,
Foster
L. J.
,
Loewen
C. J.
(
2014
).
Polarization of the endoplasmic reticulum by ER-septin tethering.
Cell
158
,
620
632
.
Chernyakov
I.
,
Santiago-Tirado
F.
,
Bretscher
A.
(
2013
).
Active segregation of yeast mitochondria by Myo2 is essential and mediated by Mmr1 and Ypt11.
Curr. Biol.
23
,
1818
1824
.
Chung
S.
,
Takizawa
P. A.
(
2010
).
Multiple Myo4 motors enhance ASH1 mRNA transport in Saccharomyces cerevisiae.
J. Cell Biol.
189
,
755
767
.
Clay
L.
,
Caudron
F.
,
Denoth-Lippuner
A.
,
Boettcher
B.
,
Buvelot Frei
S.
,
Snapp
E. L.
,
Barral
Y.
(
2014
).
A sphingolipid-dependent diffusion barrier confines ER stress to the yeast mother cell.
eLife
3
,
e01883
.
Colombi
P.
,
Webster
B. M.
,
Fröhlich
F.
,
Lusk
C. P.
(
2013
).
The transmission of nuclear pore complexes to daughter cells requires a cytoplasmic pool of Nsp1.
J. Cell Biol.
203
,
215
232
.
David
C.
,
Koch
J.
,
Oeljeklaus
S.
,
Laernsack
A.
,
Melchior
S.
,
Wiese
S.
,
Schummer
A.
,
Erdmann
R.
,
Warscheid
B.
,
Brocard
C.
(
2013
).
A combined approach of quantitative interaction proteomics and live-cell imaging reveals a regulatory role for endoplasmic reticulum (ER) reticulon homology proteins in peroxisome biogenesis.
Mol. Cell. Proteomics
12
,
2408
2425
.
Delille
H. K.
,
Alves
R.
,
Schrader
M.
(
2009
).
Biogenesis of peroxisomes and mitochondria: linked by division.
Histochem. Cell Biol.
131
,
441
446
.
Du
Y.
,
Pypaert
M.
,
Novick
P.
,
Ferro-Novick
S.
(
2001
).
Aux1p/Swa2p is required for cortical endoplasmic reticulum inheritance in Saccharomyces cerevisiae.
Mol. Biol. Cell
12
,
2614
2628
.
Elbaz-Alon
Y.
,
Rosenfeld-Gur
E.
,
Shinder
V.
,
Futerman
A. H.
,
Geiger
T.
,
Schuldiner
M.
(
2014
).
A dynamic interface between vacuoles and mitochondria in yeast.
Dev. Cell
30
,
95
102
.
Erjavec
N.
,
Nyström
T.
(
2007
).
Sir2p-dependent protein segregation gives rise to a superior reactive oxygen species management in the progeny of Saccharomyces cerevisiae.
Proc. Natl. Acad. Sci. USA
104
,
10877
10881
.
Estrada
P.
,
Kim
J.
,
Coleman
J.
,
Walker
L.
,
Dunn
B.
,
Takizawa
P.
,
Novick
P.
,
Ferro-Novick
S.
(
2003
).
Myo4p and She3p are required for cortical ER inheritance in Saccharomyces cerevisiae.
J. Cell Biol.
163
,
1255
1266
.
Evangelista
M.
,
Pruyne
D.
,
Amberg
D. C.
,
Boone
C.
,
Bretscher
A.
(
2002
).
Formins direct Arp2/3-independent actin filament assembly to polarize cell growth in yeast.
Nat. Cell Biol.
4
,
32
41
.
Eves
P. T.
,
Jin
Y.
,
Brunner
M.
,
Weisman
L. S.
(
2012
).
Overlap of cargo binding sites on myosin V coordinates the inheritance of diverse cargoes.
J. Cell Biol.
198
,
69
85
.
Fagarasanu
M.
,
Fagarasanu
A.
,
Tam
Y. Y. C.
,
Aitchison
J. D.
,
Rachubinski
R. A.
(
2005
).
Inp1p is a peroxisomal membrane protein required for peroxisome inheritance in Saccharomyces cerevisiae.
J. Cell Biol.
169
,
765
775
.
Fagarasanu
A.
,
Fagarasanu
M.
,
Eitzen
G. A.
,
Aitchison
J. D.
,
Rachubinski
R. A.
(
2006
).
The peroxisomal membrane protein Inp2p is the peroxisome-specific receptor for the myosin V motor Myo2p of Saccharomyces cerevisiae.
Dev. Cell
10
,
587
600
.
Fagarasanu
A.
,
Fagarasanu
M.
,
Rachubinski
R. A.
(
2007
).
Maintaining peroxisome populations: a story of division and inheritance.
Annu. Rev. Cell Dev. Biol.
23
,
321
344
.
Fagarasanu
A.
,
Mast
F. D.
,
Knoblach
B.
,
Jin
Y.
,
Brunner
M. J.
,
Logan
M. R.
,
Glover
J. N.
,
Eitzen
G. A.
,
Aitchison
J. D.
,
Weisman
L. S.
et al. (
2009
).
Myosin-driven peroxisome partitioning in S. cerevisiae.
J. Cell Biol.
186
,
541
554
.
Fagarasanu
A.
,
Mast
F. D.
,
Knoblach
B.
,
Rachubinski
R. A.
(
2010
).
Molecular mechanisms of organelle inheritance: lessons from peroxisomes in yeast.
Nat. Rev. Mol. Cell Biol.
11
,
644
654
.
Falcón
A. A.
,
Aris
J. P.
(
2003
).
Plasmid accumulation reduces life span in Saccharomyces cerevisiae.
J. Biol. Chem.
278
,
41607
41617
.
Fehrenbacher
K. L.
,
Yang
H. C.
,
Gay
A. C.
,
Huckaba
T. M.
,
Pon
L. A.
(
2004
).
Live cell imaging of mitochondrial movement along actin cables in budding yeast.
Curr. Biol.
14
,
1996
2004
.
Förtsch
J.
,
Hummel
E.
,
Krist
M.
,
Westermann
B.
(
2011
).
The myosin-related motor protein Myo2 is an essential mediator of bud-directed mitochondrial movement in yeast.
J. Cell Biol.
194
,
473
488
.
Frederick
R. L.
,
Okamoto
K.
,
Shaw
J. M.
(
2008
).
Multiple pathways influence mitochondrial inheritance in budding yeast.
Genetics
178
,
825
837
.
Friedman
J. R.
,
Nunnari
J.
(
2014
).
Mitochondrial form and function.
Nature
505
,
335
343
.
Friedman
J. R.
,
Lackner
L. L.
,
West
M.
,
DiBenedetto
J. R.
,
Nunnari
J.
,
Voeltz
G. K.
(
2011
).
ER tubules mark sites of mitochondrial division.
Science
334
,
358
362
.
Gehlen
L. R.
,
Nagai
S.
,
Shimada
K.
,
Meister
P.
,
Taddei
A.
,
Gasser
S. M.
(
2011
).
Nuclear geometry and rapid mitosis ensure asymmetric episome segregation in yeast.
Curr. Biol.
21
,
25
33
.
Heil-Chapdelaine
R. A.
,
Oberle
J. R.
,
Cooper
J. A.
(
2000
).
The cortical protein Num1p is essential for dynein-dependent interactions of microtubules with the cortex.
J. Cell Biol.
151
,
1337
1344
.
Henderson
K. A.
,
Hughes
A. L.
,
Gottschling
D. E.
(
2014
).
Mother-daughter asymmetry of pH underlies aging and rejuvenation in yeast.
eLife
3
,
e03504
.
Hermann
G. J.
,
Thatcher
J. W.
,
Mills
J. P.
,
Hales
K. G.
,
Fuller
M. T.
,
Nunnari
J.
,
Shaw
J. M.
(
1998
).
Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p.
J. Cell Biol.
143
,
359
373
.
Higuchi
R.
,
Vevea
J. D.
,
Swayne
T. C.
,
Chojnowski
R.
,
Hill
V.
,
Boldogh
I. R.
,
Pon
L. A.
(
2013
).
Actin dynamics affect mitochondrial quality control and aging in budding yeast.
Curr. Biol.
23
,
2417
2422
.
Higuchi-Sanabria
R.
,
Pernice
W. M.
,
Vevea
J. D.
,
Alessi Wolken
D. M.
,
Boldogh
I. R.
,
Pon
L. A.
(
2014
).
Role of asymmetric cell division in lifespan control in Saccharomyces cerevisiae.
FEMS Yeast Res
(
in press
)
Hill
S. M.
,
Hao
X.
,
Liu
B.
,
Nyström
T.
(
2014
).
Life-span extension by a metacaspase in the yeast Saccharomyces cerevisiae.
Science
344
,
1389
1392
.
Hobbs
A. E.
,
Srinivasan
M.
,
McCaffery
J. M.
,
Jensen
R. E.
(
2001
).
Mmm1p, a mitochondrial outer membrane protein, is connected to mitochondrial DNA (mtDNA) nucleoids and required for mtDNA stability.
J. Cell Biol.
152
,
401
410
.
Hoepfner
D.
,
van den Berg
M.
,
Philippsen
P.
,
Tabak
H. F.
,
Hettema
E. H.
(
2001
).
A role for Vps1p, actin, and the Myo2p motor in peroxisome abundance and inheritance in Saccharomyces cerevisiae.
J. Cell Biol.
155
,
979
990
.
Hoepfner
D.
,
Schildknegt
D.
,
Braakman
I.
,
Philippsen
P.
,
Tabak
H. F.
(
2005
).
Contribution of the endoplasmic reticulum to peroxisome formation.
Cell
122
,
85
95
.
Hönscher
C.
,
Mari
M.
,
Auffarth
K.
,
Bohnert
M.
,
Griffith
J.
,
Geerts
W.
,
van der Laan
M.
,
Cabrera
M.
,
Reggiori
F.
,
Ungermann
C.
(
2014
).
Cellular metabolism regulates contact sites between vacuoles and mitochondria.
Dev. Cell
30
,
86
94
.
Hoppins
S.
,
Collins
S. R.
,
Cassidy-Stone
A.
,
Hummel
E.
,
Devay
R. M.
,
Lackner
L. L.
,
Westermann
B.
,
Schuldiner
M.
,
Weissman
J. S.
,
Nunnari
J.
(
2011
).
A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria.
J. Cell Biol.
195
,
323
340
.
Huckaba
T. M.
,
Lipkin
T.
,
Pon
L. A.
(
2006
).
Roles of type II myosin and a tropomyosin isoform in retrograde actin flow in budding yeast.
J. Cell Biol.
175
,
957
969
.
Huffaker
T. C.
,
Thomas
J. H.
,
Botstein
D.
(
1988
).
Diverse effects of β-tubulin mutations on microtubule formation and function.
J. Cell Biol.
106
,
1997
2010
.
Hughes
A. L.
,
Gottschling
D. E.
(
2012
).
An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast.
Nature
492
,
261
265
.
Ingerman
E.
,
Perkins
E. M.
,
Marino
M.
,
Mears
J. A.
,
McCaffery
J. M.
,
Hinshaw
J. E.
,
Nunnari
J.
(
2005
).
Dnm1 forms spirals that are structurally tailored to fit mitochondria.
J. Cell Biol.
170
,
1021
1027
.
Ishikawa
K.
,
Catlett
N. L.
,
Novak
J. L.
,
Tang
F.
,
Nau
J. J.
,
Weisman
L. S.
(
2003
).
Identification of an organelle-specific myosin V receptor.
J. Cell Biol.
160
,
887
897
.
Itoh
T.
,
Watabe
A.
,
Toh-E
A.
,
Matsui
Y.
(
2002
).
Complex formation with Ypt11p, a rab-type small GTPase, is essential to facilitate the function of Myo2p, a class V myosin, in mitochondrial distribution in Saccharomyces cerevisiae.
Mol. Cell. Biol.
22
,
7744
7757
.
Itoh
T.
,
Toh-E
A.
,
Matsui
Y.
(
2004
).
Mmr1p is a mitochondrial factor for Myo2p-dependent inheritance of mitochondria in the budding yeast.
EMBO J.
23
,
2520
2530
.
Jacobs
C. W.
,
Adams
A. E.
,
Szaniszlo
P. J.
,
Pringle
J. R.
(
1988
).
Functions of microtubules in the Saccharomyces cerevisiae cell cycle.
J. Cell Biol.
107
,
1409
1426
.
Jacquier
N.
,
Choudhary
V.
,
Mari
M.
,
Toulmay
A.
,
Reggiori
F.
,
Schneiter
R.
(
2011
).
Lipid droplets are functionally connected to the endoplasmic reticulum in Saccharomyces cerevisiae.
J. Cell Sci.
124
,
2424
2437
.
Jin
Y.
,
Sultana
A.
,
Gandhi
P.
,
Franklin
E.
,
Hamamoto
S.
,
Khan
A. R.
,
Munson
M.
,
Schekman
R.
,
Weisman
L. S.
(
2011
).
Myosin V transports secretory vesicles via a Rab GTPase cascade and interaction with the exocyst complex.
Dev. Cell
21
,
1156
1170
.
Kaganovich
D.
,
Kopito
R.
,
Frydman
J.
(
2008
).
Misfolded proteins partition between two distinct quality control compartments.
Nature
454
,
1088
1095
.
Khmelinskii
A.
,
Keller
P. J.
,
Lorenz
H.
,
Schiebel
E.
,
Knop
M.
(
2010
).
Segregation of yeast nuclear pores.
Nature
466
,
E1
E2
.
Klecker
T.
,
Scholz
D.
,
Förtsch
J.
,
Westermann
B.
(
2013
).
The yeast cell cortical protein Num1 integrates mitochondrial dynamics into cellular architecture.
J. Cell Sci.
126
,
2924
2930
.
Klecker
T.
,
Böckler
S.
,
Westermann
B.
(
2014
).
Making connections: interorganelle contacts orchestrate mitochondrial behavior.
Trends Cell Biol.
24
,
537
545
.
Knoblach
B.
,
Rachubinski
R. A.
(
2013
).
Doing the math: How yeast cells maintain their peroxisome populations.
Commun. Integr. Biol.
6
,
e26901
.
Knoblach
B.
,
Rachubinski
R. A.
(
2014
).
Transport and retention mechanisms govern lipid droplet inheritance in Saccharomyces cerevisiae.
Traffic
doi: 10.1111/tra.12247
Knoblach
B.
,
Sun
X.
,
Coquelle
N.
,
Fagarasanu
A.
,
Poirier
R. L.
,
Rachubinski
R. A.
(
2013
).
An ER-peroxisome tether exerts peroxisome population control in yeast.
EMBO J.
32
,
2439
2453
.
Koch
J.
,
Pranjic
K.
,
Huber
A.
,
Ellinger
A.
,
Hartig
A.
,
Kragler
F.
,
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.
,
Walter
P.
(
2009
).
An ER-mitochondria tethering complex revealed by a synthetic biology screen.
Science
325
,
477
481
.
Kuravi
K.
,
Nagotu
S.
,
Krikken
A. M.
,
Sjollema
K.
,
Deckers
M.
,
Erdmann
R.
,
Veenhuis
M.
,
van der Klei
I. J.
(
2006
).
Dynamin-related proteins Vps1p and Dnm1p control peroxisome abundance in Saccharomyces cerevisiae.
J. Cell Sci.
119
,
3994
4001
.
Lackner
L. L.
,
Ping
H.
,
Graef
M.
,
Murley
A.
,
Nunnari
J.
(
2013
).
Endoplasmic reticulum-associated mitochondria-cortex tether functions in the distribution and inheritance of mitochondria.
Proc. Natl. Acad. Sci. USA
110
,
E458
E467
.
Lewandowska
A.
,
Macfarlane
J.
,
Shaw
J. M.
(
2013
).
Mitochondrial association, protein phosphorylation, and degradation regulate the availability of the active Rab GTPase Ypt11 for mitochondrial inheritance.
Mol. Biol. Cell
24
,
1185
1195
.
Lindstrom
D. L.
,
Leverich
C. K.
,
Henderson
K. A.
,
Gottschling
D. E.
(
2011
).
Replicative age induces mitotic recombination in the ribosomal RNA gene cluster of Saccharomyces cerevisiae.
PLoS Genet.
7
,
e1002015
.
Lipatova
Z.
,
Tokarev
A. A.
,
Jin
Y.
,
Mulholland
J.
,
Weisman
L. S.
,
Segev
N.
(
2008
).
Direct interaction between a myosin V motor and the Rab GTPases Ypt31/32 is required for polarized secretion.
Mol. Biol. Cell
19
,
4177
4187
.
Liu
B.
,
Larsson
L.
,
Caballero
A.
,
Hao
X.
,
Oling
D.
,
Grantham
J.
,
Nyström
T.
(
2010
).
The polarisome is required for segregation and retrograde transport of protein aggregates.
Cell
140
,
257
267
.
Luedeke
C.
,
Frei
S. B.
,
Sbalzarini
I.
,
Schwarz
H.
,
Spang
A.
,
Barral
Y.
(
2005
).
Septin-dependent compartmentalization of the endoplasmic reticulum during yeast polarized growth.
J. Cell Biol.
169
,
897
908
.
Makio
T.
,
Lapetina
D. L.
,
Wozniak
R. W.
(
2013
).
Inheritance of yeast nuclear pore complexes requires the Nsp1p subcomplex.
J. Cell Biol.
203
,
187
196
.
Manford
A. G.
,
Stefan
C. J.
,
Yuan
H. L.
,
Macgurn
J. A.
,
Emr
S. D.
(
2012
).
ER-to-plasma membrane tethering proteins regulate cell signaling and ER morphology.
Dev. Cell
23
,
1129
1140
.
McCormick
M. A.
,
Mason
A. G.
,
Guyenet
S. J.
,
Dang
W.
,
Garza
R. M.
,
Ting
M. K.
,
Moller
R. M.
,
Berger
S. L.
,
Kaeberlein
M.
,
Pillus
L.
et al. (
2014
).
The SAGA histone deubiquitinase module controls yeast replicative lifespan via Sir2 interaction.
Cell Reports
8
,
477
486
.
McFaline-Figueroa
J. R.
,
Vevea
J.
,
Swayne
T. C.
,
Zhou
C.
,
Liu
C.
,
Leung
G.
,
Boldogh
I. R.
,
Pon
L. A.
(
2011
).
Mitochondrial quality control during inheritance is associated with lifespan and mother-daughter age asymmetry in budding yeast.
Aging Cell
10
,
885
895
.
Meeusen
S.
,
Nunnari
J.
(
2003
).
Evidence for a two membrane-spanning autonomous mitochondrial DNA replisome.
J. Cell Biol.
163
,
503
510
.
Menendez-Benito
V.
,
van Deventer
S. J.
,
Jimenez-Garcia
V.
,
Roy-Luzarraga
M.
,
van Leeuwen
F.
,
Neefjes
J.
(
2013
).
Spatiotemporal analysis of organelle and macromolecular complex inheritance.
Proc. Natl. Acad. Sci. USA
110
,
175
180
.
Motley
A. M.
,
Hettema
E. H.
(
2007
).
Yeast peroxisomes multiply by growth and division.
J. Cell Biol.
178
,
399
410
.
Mozdy
A. D.
,
McCaffery
J. M.
,
Shaw
J. M.
(
2000
).
Dnm1p GTPase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p.
J. Cell Biol.
151
,
367
380
.
Munck
J. M.
,
Motley
A. M.
,
Nuttall
J. M.
,
Hettema
E. H.
(
2009
).
A dual function for Pex3p in peroxisome formation and inheritance.
J. Cell Biol.
187
,
463
471
.
Murley
A.
,
Lackner
L. L.
,
Osman
C.
,
West
M.
,
Voeltz
G. K.
,
Walter
P.
,
Nunnari
J.
(
2013
).
ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast.
eLife
2
,
e00422
.
Ouellet
J.
,
Barral
Y.
(
2012
).
Organelle segregation during mitosis: lessons from asymmetrically dividing cells.
J. Cell Biol.
196
,
305
313
.
Pashkova
N.
,
Jin
Y.
,
Ramaswamy
S.
,
Weisman
L. S.
(
2006
).
Structural basis for myosin V discrimination between distinct cargoes.
EMBO J.
25
,
693
700
.
Peng
Y.
,
Weisman
L. S.
(
2008
).
The cyclin-dependent kinase Cdk1 directly regulates vacuole inheritance.
Dev. Cell
15
,
478
485
.
Pfanner
N.
,
van der Laan
M.
,
Amati
P.
,
Capaldi
R. A.
,
Caudy
A. A.
,
Chacinska
A.
,
Darshi
M.
,
Deckers
M.
,
Hoppins
S.
,
Icho
T.
et al. (
2014
).
Uniform nomenclature for the mitochondrial contact site and cristae organizing system.
J. Cell Biol.
204
,
1083
1086
.
Prinz
W. A.
(
2014
).
Bridging the gap: membrane contact sites in signaling, metabolism, and organelle dynamics.
J. Cell Biol.
205
,
759
769
.
Pruyne
D.
,
Evangelista
M.
,
Yang
C.
,
Bi
E.
,
Zigmond
S.
,
Bretscher
A.
,
Boone
C.
(
2002
).
Role of formins in actin assembly: nucleation and barbed-end association.
Science
297
,
612
615
.
Rafelski
S. M.
,
Viana
M. P.
,
Zhang
Y.
,
Chan
Y. H.
,
Thorn
K. S.
,
Yam
P.
,
Fung
J. C.
,
Li
H.
,
Costa
L. F.
,
Marshall
W. F.
(
2012
).
Mitochondrial network size scaling in budding yeast.
Science
338
,
822
824
.
Rossanese
O. W.
,
Reinke
C. A.
,
Bevis
B. J.
,
Hammond
A. T.
,
Sears
I. B.
,
O'Connor
J.
,
Glick
B. S.
(
2001
).
A role for actin, Cdc1p, and Myo2p in the inheritance of late Golgi elements in Saccharomyces cerevisiae.
J. Cell Biol.
153
,
47
62
.
Rowland
A. A.
,
Voeltz
G. K.
(
2012
).
Endoplasmic reticulum-mitochondria contacts: function of the junction.
Nat. Rev. Mol. Cell Biol.
13
,
607
625
.
Sagot
I.
,
Rodal
A. A.
,
Moseley
J.
,
Goode
B. L.
,
Pellman
D.
(
2002
).
An actin nucleation mechanism mediated by Bni1 and profilin.
Nat. Cell Biol.
4
,
626
631
.
Santiago-Tirado
F. H.
,
Legesse-Miller
A.
,
Schott
D.
,
Bretscher
A.
(
2011
).
PI4P and Rab inputs collaborate in myosin-V-dependent transport of secretory compartments in yeast.
Dev. Cell
20
,
47
59
.
Scheckhuber
C. Q.
,
Erjavec
N.
,
Tinazli
A.
,
Hamann
A.
,
Nyström
T.
,
Osiewacz
H. D.
(
2007
).
Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models.
Nat. Cell Biol.
9
,
99
105
.
Scheckhuber
C. Q.
,
Wanger
R. A.
,
Mignat
C. A.
,
Osiewacz
H. D.
(
2011
).
Unopposed mitochondrial fission leads to severe lifespan shortening.
Cell Cycle
10
,
3105
3110
.
Schmid
M.
,
Jaedicke
A.
,
Du
T. G.
,
Jansen
R. P.
(
2006
).
Coordination of endoplasmic reticulum and mRNA localization to the yeast bud.
Curr. Biol.
16
,
1538
1543
.
Schrader
M.
,
Bonekamp
N. A.
,
Islinger
M.
(
2012
).
Fission and proliferation of peroxisomes.
Biochim. Biophys. Acta
1822
,
1343
1357
.
Sellers
J. R.
,
Veigel
C.
(
2006
).
Walking with myosin V. Curr.
Opin. Cell Biol.
18
,
68
73
.
Sesaki
H.
,
Jensen
R. E.
(
1999
).
Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape.
J. Cell Biol.
147
,
699
706
.
Shcheprova
Z.
,
Baldi
S.
,
Frei
S. B.
,
Gonnet
G.
,
Barral
Y.
(
2008
).
A mechanism for asymmetric segregation of age during yeast budding.
Nature
454
,
728
734
.
Shepard
K. A.
,
Gerber
A. P.
,
Jambhekar
A.
,
Takizawa
P. A.
,
Brown
P. O.
,
Herschlag
D.
,
DeRisi
J. L.
,
Vale
R. D.
(
2003
).
Widespread cytoplasmic mRNA transport in yeast: identification of 22 bud-localized transcripts using DNA microarray analysis.
Proc. Natl. Acad. Sci. USA
100
,
11429
11434
.
Sinclair
D. A.
,
Guarente
L.
(
1997
).
Extrachromosomal rDNA circles – a cause of aging in yeast.
Cell
91
,
1033
1042
.
Sinclair
D. A.
,
Mills
K.
,
Guarente
L.
(
1998
).
Molecular mechanisms of yeast aging.
Trends Biochem. Sci.
23
,
131
134
.
Song
J.
,
Yang
Q.
,
Yang
J.
,
Larsson
L.
,
Hao
X.
,
Zhu
X.
,
Malmgren-Hill
S.
,
Cvijovic
M.
,
Fernandez-Rodriguez
J.
,
Grantham
J.
et al. (
2014
).
Essential genetic interactors of SIR2 required for spatial sequestration and asymmetrical inheritance of protein aggregates.
PLoS Genet.
10
,
e1004539
.
Spokoini
R.
,
Moldavski
O.
,
Nahmias
Y.
,
England
J. L.
,
Schuldiner
M.
,
Kaganovich
D.
(
2012
).
Confinement to organelle-associated inclusion structures mediates asymmetric inheritance of aggregated protein in budding yeast.
Cell Reports
2
,
738
747
.
Stefan
C. J.
,
Manford
A. G.
,
Emr
S. D.
(
2013
).
ER-PM connections: sites of information transfer and inter-organelle communication.
Curr. Opin. Cell Biol.
25
,
434
442
.
Swayne
T. C.
,
Zhou
C.
,
Boldogh
I. R.
,
Charalel
J. K.
,
McFaline-Figueroa
J. R.
,
Thoms
S.
,
Yang
C.
,
Leung
G.
,
McInnes
J.
,
Erdmann
R.
et al. (
2011
).
Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.
Curr. Biol.
21
,
1994
1999
.
Tang
F.
,
Kauffman
E. J.
,
Novak
J. L.
,
Nau
J. J.
,
Catlett
N. L.
,
Weisman
L. S.
(
2003
).
Regulated degradation of a class V myosin receptor directs movement of the yeast vacuole.
Nature
422
,
87
92
.
Thoms
S.
,
Harms
I.
,
Kalies
K. U.
,
Gärtner
J.
(
2012
).
Peroxisome formation requires the endoplasmic reticulum channel protein Sec61.
Traffic
13
,
599
609
.
Toulmay
A.
,
Prinz
W. A.
(
2012
).
A conserved membrane-binding domain targets proteins to organelle contact sites.
J. Cell Sci.
125
,
49
58
.
Vevea
J. D.
,
Wolken
D. M.
,
Swayne
T. C.
,
White
A. B.
,
Pon
L. A.
(
2013
).
Ratiometric biosensors that measure mitochondrial redox state and ATP in living yeast cells.
J. Vis. Exp.
77
,
22
.
Vevea
J. D.
,
Swayne
T. C.
,
Boldogh
I. R.
,
Pon
L. A.
(
2014
).
Inheritance of the fittest mitochondria in yeast.
Trends Cell Biol.
24
,
53
60
.
Weisman
L. S.
(
2006
).
Organelles on the move: insights from yeast vacuole inheritance.
Nat. Rev. Mol. Cell Biol.
7
,
243
252
.
Westermann
B.
(
2014
).
Mitochondrial inheritance in yeast.
Biochim. Biophys. Acta
1837
,
1039
1046
.
Wolf
W.
,
Kilic
A.
,
Schrul
B.
,
Lorenz
H.
,
Schwappach
B.
,
Seedorf
M.
(
2012
).
Yeast Ist2 recruits the endoplasmic reticulum to the plasma membrane and creates a ribosome-free membrane microcompartment.
PLoS ONE
7
,
e39703
.
Wolinski
H.
,
Kolb
D.
,
Hermann
S.
,
Koning
R. I.
,
Kohlwein
S. D.
(
2011
).
A role for seipin in lipid droplet dynamics and inheritance in yeast.
J. Cell Sci.
124
,
3894
3904
.
Yaffe
M. P.
(
1999
).
The machinery of mitochondrial inheritance and behavior.
Science
283
,
1493
1497
.
Yan
M.
,
Rachubinski
D. A.
,
Joshi
S.
,
Rachubinski
R. A.
,
Subramani
S.
(
2008
).
Dysferlin domain-containing proteins, Pex30p and Pex31p, localized to two compartments, control the number and size of oleate-induced peroxisomes in Pichia pastoris.
Mol. Biol. Cell
19
,
885
898
.
Yang
H. C.
,
Palazzo
A.
,
Swayne
T. C.
,
Pon
L. A.
(
1999
).
A retention mechanism for distribution of mitochondria during cell division in budding yeast.
Curr. Biol.
9
,
1111
1114, S1-S2
.
Yau
R. G.
,
Peng
Y.
,
Valiathan
R. R.
,
Birkeland
S. R.
,
Wilson
T. E.
,
Weisman
L. S.
(
2014
).
Release from myosin V via regulated recruitment of an E3 ubiquitin ligase controls organelle localization.
Dev. Cell
28
,
520
533
.
Yin
H.
,
Pruyne
D.
,
Huffaker
T. C.
,
Bretscher
A.
(
2000
).
Myosin V orientates the mitotic spindle in yeast.
Nature
406
,
1013
1015
.

Competing interests

The authors declare no competing or financial interests.