The role of metabolism in cellular quiescence

Cellular quiescence is a dormant state where typically undifferentiated cells stop dividing and reduce many aspects of cellular activity (Rumman et al., 2015; Montarras et al., 2013). However, not all non-dividing cells are in a state of quiescence (for example, terminally differentiated or senescent cells). Cellular quiescence is evolutionarily conserved from bacteria to mammalian cells, and although some of the details of quiescent cells can vary between systems, truly dormant quiescent cells share several key characteristics. First, quiescent cells can resume activity and re-enter the cell cycle, which separates them from other non-dividing cells (Fig. 1A) (Rumman et al., 2015; Montarras et al., 2013). In this regard, quiescence is a survival strategy for very long-lived cells, such as oocytes and spores, that protects them until they receive the proper cue to drive development (Sieber et al., 2016; Hocaoglu et al., 2021). Second, transcription and translation are dramatically suppressed in quiescent cells (Fig. 1B) (Lovett and Goldstein, 1977; Mermod et al., 1977; Susor et al., 2015; Zismanov et al., 2016). Given that quiescent cells are dormant, and have no biosynthetic requirement for growth, these cells maintain minimal gene expression activity. Third, quiescent cells reprogram their metabolic system to maintain low metabolic activity (Simsek et al., 2010; Suda et al., 2011; Valcourt et al., 2012). Compared to their proliferating counterparts, quiescent cells have distinct metabolic profiles involving changes in major metabolic pathways, including glycolysis (Sieber et al., 2016; Hocaoglu et al., 2021), glutaminolysis, the pentose phosphate pathway (Coller, 2019), fatty acid oxidation (Ortmayr and Zampieri, 2022), the tricarboxylic acid (TCA) cycle (Sieber et al., 2016), oxidative phosphorylation (Sieber et al., 2016) and one-carbon metabolism (Fig. 2) (Valcourt et al., 2012). All these changes allow cells to maintain their quiescent status by providing necessary biosynthesis and energy production activity, while at the same time reducing reactive oxygen species (ROS) production to prevent oxidative damage during prolonged periods of quiescence.

The term ‘quiescence’ has been used quite loosely in the literature. Many studies have defined quiescence as an arrested cellular status with the capacity to divide again, without considering the physiology (van Velthoven and Rando, 2019; Rumman et al., 2015; Hocaoglu et al., 2021). Under this definition, hepatocytes and neurons are recognized as quiescent cells. However, it is common knowledge that although these cells do not divide, they are not dormant and display high levels of activity. Indeed, quiescent cells exist on a spectrum ranging from deeply dormant oocytes and spores to more transiently dormant adult stem cells (Fig. 1B). As a result, although aspects of quiescence are consistent among populations of quiescent cells, individual aspects of their physiology might vary based on lineage and the cellular microenvironment. When examining the physiological aspects of cellular quiescence, it is also important to note that quiescence can be part of a developmental program or induced by stresses, such as starvation (Sieber et al., 2016; Lovett and Goldstein, 1977; Mermod et al., 1977; Ohtsuka et al., 2022). For instance, oocytes and stem cells enter quiescence as part of a normal developmental strategy (Rumman et al., 2015; Kim and You, 2022). However, spores and cancer cells enter quiescence under periods of cellular stress. In particular, starvation and defects in nutrient utilization are commonly associated with induced forms of quiescence (Ohtsuka et al., 2022) (Fig. 1A). In this Review, we examine the metabolic characteristics of both dormant and transiently quiescent cells and examine how the metabolic state of quiescent cells impacts aging and disease progression.

Through a series of transcriptional, translational and metabolic changes, quiescence supports a diverse array of biological processes including oogenesis, (Kim and You, 2022) tissue regeneration (van Velthoven and Rando, 2019) and chemotherapy resistance (Brown and Schober, 2018). For example, quiescence protects oocytes from oxidative damage and promotes nutrient storage (Sieber et al., 2016), which gives oocytes the capacity to exist for prolonged periods (up to decades) until fertilization, by creating a physiological state that maintains developmental competence and supports growth after fertilization.

Similarly, many adult stem cells are kept in a quiescent state, poised for activation, until induced by injury and their proliferation drives regeneration and wound repair (Montarras et al., 2013; Urban and Cheung, 2021). Maintaining quiescence is crucial for maintaining epithelial integrity and reducing the risk of epithelial cancer (Tomasin and Bruni-Cardoso, 2022; Luo et al., 2020). Stem cells that lose the ability to maintain quiescence are a major cause of many forms of cancer. This protective program of quiescence can also be hijacked by cancer cells, which enter quiescence and evade traditional radiation and chemotherapy approaches (Lee et al., 2020; Nik Nabil et al., 2021). This strategy gives rise to aggressive secondary tumors in many recurrent forms of cancer^28,29. Despite these important roles for quiescence in development, wound repair and cancer, surprisingly little is known about how metabolic pathways support cellular quiescence.

Spores and oocytes are deeply dormant quiescent cells that survive in this protective state for decades (Adhikari et al., 2010; McLaughlin and McIver, 2009). These cells have extremely low metabolic activity that prevents oxidative damage and maintains nutrient stores for these extended periods (Sieber et al., 2016). For example, metabolism of endogenous compounds in Bacillus spores, including 3-phosphoglyceric acid (3PGA), ribonucleotides and ATP, could not be detected by 31P nuclear magnetic resonance (NMR) over a 30-day period (Ghosh et al., 2015). Different strategies have been used by spores to maintain their low metabolic activity. The first strategy is to alter electron transport chain (ETC) assembly to suppress respiration (Fig. 2). In Botryodiplodia spores, some subunits of the cytochrome c oxidase complex (complex IV) are removed from the mitochondrial inner membrane to be preserved in the cytosol. In the early minutes of germination, these preserved polypeptides re-enter the mitochondria and assemble to restore complex IV activity (Stade and Brambl, 1981; Brambl and Josephson, 1977; Brambl, 1980) . The ATPase complex function is restored by assembling new complexes from subunits that are translated from mRNA preserved in the dormant spores. The second strategy is the downregulation of carbohydrate catabolic pathways and accumulation of stored carbohydrates. During spore formation, yeast accumulate a variety of carbohydrates, including trehalose, glycogen and mannose, suggesting a shift of carbohydrates from catabolism to anabolism (François and Parrou, 2001; Liu et al., 2020). Studies in yeast have suggested this carbohydrate accumulation aids in protection from a wide variety of stresses (Tapia et al., 2015; Tapia and Koshland, 2014; Bandara et al., 2009); increased carbohydrate storage is proposed to prevent the freezing of cytosol in low-temperature conditions and prevent protein aggregation and membrane damage cause by other stresses. However, direct evidence for these ideas remains limited.

Interestingly, systematic studies of Drosophila oogenesis have shown that quiescent oocytes share many metabolic characteristics similar to quiescent spores (Mermod et al., 1977; Lovett and Goldstein, 1977; Sieber et al., 2016). Mitochondrial activity decreases ∼90–95%, and oocytes display a dramatic 38-fold increase in stored glycogen (Sieber et al., 2016; Hocaoglu et al., 2021). During mid-oogenesis, mitochondria in the germ cell of stage 10 follicles enter a state of mitochondrial respiratory quiescence (MRQ). MRQ is triggered by reduced insulin and AKT signaling in germ cells during late oogenesis. Loss of insulin signal activates the key effector kinase glycogen synthase kinase 3 (GSK3, which has GSK3A and GSK3B forms in mammals), which induces a shift in the mitochondrial proteome and ETC remodeling (Sieber et al., 2016).

During quiescence, GSK3 localizes to the mitochondria and phosphorylates mitochondrial outer membrane proteins, such as TOMM22, TOMM40 and voltage-dependent anion channel (VDAC) proteins. Once phosphorylated, the proteasome is recruited to the mitochondrial surface (Yue et al., 2022). A subset of the outer membrane proteins is degraded, which triggers remodeling of the ETC. During ETC remodeling, the amount of assembled complex I and V decline dramatically. Simultaneously, the mitochondria become fragmented, and the mitochondrial cristae become hard to observe by electron microscopy (Sieber et al., 2016). This is consistent with observations showing that subunits of complex IV are displaced from the mitochondrial inner membrane during fungal sporulation (Brambl and Josephson, 1977; Brambl, 1980; Stade and Brambl, 1981). This fundamental remodeling of the mitochondria causes a shift in metabolic flux, including a substantial increase in TCA cycle intermediates and a shift in the balance between glycolysis suppression and increased levels of gluconeogenesis in mature quiescent oocytes. This significantly increases glycogen storage, a feature that is also conserved in Xenopus oocytes (Sieber et al., 2016).

Unlike spores and Drosophila oocytes, which provide all the nutrients for development, mammalian oocytes only store enough nutrients to support early embryogenesis; however, they do display the same suppression of mitochondrial activity that is seen in spores and Drosophila oocytes (Boell and Nicholas, 1948; Fridhandler et al., 1956). In fact, vertebrate oocytes display the same loss of complex I activity that was previously reported in Drosophila (Rodriguez-Nuevo et al., 2022). During mammalian development, the oocyte enters a quiescent germinal vesicle (GV) stage characterized by a large central nucleus surrounded by a single, incomplete layer of flat follicular cells. During this time, oocytes display a similar suppression of mitochondrial respiration (Boell and Nicholas, 1948; Fridhandler et al., 1956; Magnusson et al., 1986). Comparing to M2 stage oocytes, the GV stage oocyte has a poor capacity for glucose uptake and a low glycolytic rate due to low phosphofructokinase (PFK) activity, as shown in bovine oocytes (Cetica et al., 2002; Sutton-McDowall et al., 2010) . Despite the lack of glycolysis in oocytes, glycolytic metabolites such as pyruvate could be transported from the surrounding somatic support cells (cumulus cells) into oocytes for further catabolism (Sutton-McDowall et al., 2010). However, studies in Drosophila indicate pyruvate is not broken down in quiescent oocytes, suggesting these observations of glucose dependence could be due to artificial culture conditions used to study culture bovine oocytes (Sieber et al., 2016). Interestingly, the activity of enzymes of the TCA cycle, such as isocitrate dehydrogenase (IDH) and malate dehydrogenase (MDH), increase in oocytes during in vitro maturation and oocyte activation (Cetica et al., 2003).

One study has shown that mouse oocytes cultured in vitro display a significant increase in pentose phosphate pathway activity during oocyte maturation and activation, suggesting that glucose flux is channeled through this pathway (Li et al., 2020). This elevated pentose phosphate activity likely supports the nucleotide biosynthesis required for early embryogenesis. In addition, it has been suggested that enhanced utilization of fatty acid oxidation in early oocyte maturation and activation leads to reduced lipid metabolic intermediates in the later phase of oocyte maturation (Dunning et al., 2014, 2010). High fatty acid oxidation activity is observed in the cumulous oocyte complex (COC) during in vitro maturation. Inhibition of fatty acid oxidation significantly reduces oocyte maturation and developmental competence, while promoting fatty acid oxidation (by supplying L-carnitine), improving oocyte development (Dunning et al., 2014, 2010). However, it remains unclear whether the oocyte or the somatic cells of the COC are reliant on fatty acid oxidation. However, these in vitro maturation experiments might not reflect the in vivo metabolic features of quiescent oocytes due to the artificial nature of the systems used.

Although most quiescent cells display low levels of mitochondrial activity when compared to their differentiated progeny, there are unique metabolic aspects of transiently quiescent cells. Unlike the deeply dormant spores and oocytes, quiescent adult stem cells, including epithelial (Blanpain and Fuchs, 2006), intestinal (Barker et al., 2008) and hematopoietic stem cells (HSCs) (Wilson et al., 2008; Cheshier et al., 1999) are in a more transient quiescent state. These cells transition in and out of quiescence dynamically over shorter periods of time, from days to weeks (Montarras et al., 2013; Rumman et al., 2015; Cho et al., 2019; van Velthoven and Rando, 2019). Certain differentiated cells, such as B cells of the immune system, could also be considered transiently quiescent, however these cells maintain much higher baseline activity than dormant quiescent cells (Jellusova et al., 2017).

A great example of these less-dormant quiescent cells are adult stem cells, which maintain homeostasis by rejuvenating, repairing and regenerating damaged tissues. To avoid molecular damage, depletion over time and to prolong their viability, stem cells enter a metabolically inactive state of quiescence (Sieber et al., 2016; Rossi et al., 2008). Although there are differences in metabolic dependencies between stem cell types, suppression of oxidative phosphorylation is a common feature of quiescent stem cells (Fig. 2) (Suda et al., 2011). This lower level of respiration prevents mitochondrial ROS production (Rodriguez-Nuevo et al., 2022) and tunes metabolism to promote long-term developmental competence of the quiescent cell (Sieber et al., 2016). Unlike oocytes, stem cells, such as HSCs, reduce mitochondrial number to lower the capacity of mitochondrial oxidative metabolism. As HSCs progress from quiescence to proliferation, mitochondrial biogenesis increases to meet the energetic and biosynthetic needs of the activating cell (Cho et al., 2006; Norddahl et al., 2011; Coller, 2019). As a result, these cells typically have higher baseline activity and elevated metabolic demands than those seen in oocytes or spores. Although mitochondrial respiration is low, these cells typically display more bias towards glycolysis (Ito et al., 2012; Takubo et al., 2013) or fatty acid oxidation. This decision to be glycolytic or consume fatty acid is likely dictated by cell lineage and cellular microenvironment.

Interestingly, mouse HSCs reside in a low oxygen niche, which forces these cells to rely on anaerobic glycolysis for energy production (Suda et al., 2011). Indeed, metabolomic analysis of HSCs highlights high levels of glycolysis (Takubo et al., 2013), supported by direct examination of glycolytic flux by C13-glucose labeling, which shows a similar trend in HSC glycolytic rate (Simsek et al., 2010; Takubo et al., 2013). However, it has also been suggested that HSCs rely on fatty acid oxidation for maintenance (Coller, 2019; van Velthoven and Rando, 2019; Rumman et al., 2015; Ito et al., 2012; Takubo et al., 2013). This point is currently unclear due to conflicting reports in the field regarding the energy substrates HSCs rely on. This likely stems from the artificial conditions required to isolate HSCs (Ito et al., 2012; Takubo et al., 2013); it is important to consider that due to cell sorting and cell culture conditions required to study HSCs, these contradictory findings might reflect differences in experimental procedure and not in vivo conditions.

In conjunction with HSCs, human mesenchymal stem cells (MSCs), which reside in a variety of tissues, are in a quiescent state before proliferation and differentiation. When comparing bone marrow-derived human MSCs with their differentiated osteoblasts, these cells display a substantial dependence on glycolysis for energy production (Yuan et al., 2019). A similar metabolic program has been reported in hair follicle stem cells (HFSCs) (Son et al., 2018).

In addition to glycolysis, other types of adult stem cells rely on oxidative phosphorylation to produce energy. For example, muscle satellite cells, the stem cells of skeletal muscle, are close to blood vessels; thus, they have abundant access to oxygen and express low levels of glycolytic genes, but higher levels of genes involved in fatty acid transport and beta-oxidation (Pala et al., 2018). Although there are limited number of mitochondria in quiescent muscle satellites cells, mitochondrial fatty acid oxidation and oxidative phosphorylation are required for their survival in a quiescent state (Pala et al., 2018; Bhattacharya et al., 2021; Bhattacharya and Scimè, 2020). Typically, most cells do not utilize their full respiratory capacity and given satellite cells display reduced mitochondrial number, these cells likely reside in a state where they lack reserved mitochondrial respiratory capacity.

All quiescent cells dramatically reduce their energy demands by suppressing translation, as up to 70% of cellular ATP is used by the translational machinery (Shore and Albert, 2022). As a result, cells can meet their metabolic demands with very low levels of mitochondrial function. Similarly, mouse neural stem cells (NSCs) in the subventricular zone (SVZ) express fatty acid oxidation enzymes, such as medium chain acyl CoA dehydrogenase (MCAD) and trifunctional protein (TFP), suggesting they might also be dependent on fatty acid oxidation (Stoll et al., 2015). Consistent with this idea, cultured NSCs rely on fatty acids to power aerobic metabolism (Stoll et al., 2015). Despite being in a dormant state, NSCs are dependent on fatty acid oxidation to survive during quiescence. NSCs likely evolved this strategy to prevent ROS production by complex I of the ETC.

In the immune system, T cells are maintained in a quiescent (resting) state until stimulated by antigens. Here, resting T cells generate most of their ATP from oxidative phosphorylation by the combined consumption of glucose and other nutrients (Fox et al., 2005). Although there is some glycolysis in quiescent T cells, glucose metabolism is limited by glucose uptake, with a glycolytic rate up to 15 times lower than that in stimulated T cells (Fox et al., 2005; Bental and Deutsch, 1993). Compared to the low glycolytic activity of T cells, quiescent dermal fibroblasts uptake high levels of glucose and are more dependent on glycolysis (McKay et al., 1983). Although all these examples of quiescent cells display low mitochondrial activity when compared to their progeny, the cell lineage and metabolic environment in the stem cell niche drives an impressive diversity in the metabolic programs utilized by quiescent stem cell populations in different tissues. Comparing these diverse arrays of transiently quiescent cells shows that suppression of mitochondrial oxidative metabolism is a broad strategy for protecting cells during quiescence. However, despite this common suppression of respiration, quiescent cells from different tissues utilize different strategies to support metabolism in these low-respiration conditions.

Many conditions that impact metabolic state have a major influence on the quiescent nature of adult stem cells. For example, metabolic syndrome, a spectrum of metabolic disorders that include diabetes, obesity and insulin resistance, reduces satellite cell number and activity, which, in turn impairs muscle regeneration and repair (Fig. 3) (Han et al., 2022). Moreover, diet-induced obesity reduces the number of HSCs in bone marrow and impairs immune function in mice (Benova and Tencerova, 2020). These studies suggest that metabolic syndrome disrupts the mechanisms that protect quiescent stem cells and causes stem cell loss and impaired stem cell activation. In mice, a high-fat diet induces intestinal stem cell hyperproliferation and enhances intestinal stem cell differentiation (Aliluev et al., 2021). This suggests that, along with disrupting the quiescent state, high-fat diets might impair stem cell activity by promoting stem cell differentiation. Similarly, metabolic syndrome in humans is associated with polycystic ovarian syndrome, reduced ovulation and infertility, suggesting that oocyte quiescence might be impacted in a similar fashion (He et al., 2019; Marchiani et al., 2021). Taken together, these data suggest that metabolic syndrome is a major factor that impacts quiescence in both wound repair and reproduction. However, it remains unclear how the metabolic state of quiescent cells is impacted by metabolic syndrome and how this contributes to an impaired function of quiescent cells remains an open question.

The metabolic profiles of quiescent cells can also change over time; during aging, mitochondrial metabolism is commonly disrupted and thought to be a primary driver of many age-associated pathologies (Fig. 3) (Srivastava, 2017; Bratic and Trifunovic, 2010). This decline in mitochondrial function is associated with reduced stem cell number, impaired stem cell function and stem cell exhaustion (Sameri et al., 2020; Ruzankina and Brown, 2007; Wan and Finkel, 2020). For example, aged HSCs display increased mitochondrial metabolism that is associated with altered stem cell activity and differentiation (Ho et al., 2017). Mouse muscle satellite cells show increased glycolysis during aging and elevated baseline mitochondrial activity, suggesting they are no longer in a fully quiescent state and have adopted the metabolic state of activated stem cells (Pala et al., 2018). An important aspect of maintaining tissue homeostasis depends on the ability of stem cells to exit quiescence when needed. With aging, stem cells have a declining capacity to exit quiescence, leading to the breakdown of tissue homeostasis and impaired wound repair and regeneration (Urban and Cheung, 2021). This failure to exit quiescence likely stems from the deeply quiescent cells transitioning to a senescent-like state that cannot be activated (Fujimaki et al., 2019). Interestingly, studies have shown a similar decline in female fertility during aging associated with reduced oocyte quality (Marchiani et al., 2021). This reduced oocyte quality might stem from a transition into a senescent state that corrupts oocyte mitochondrial metabolism and impairs developmental competence (Secomandi et al., 2022). Overall, these studies highlight the profound relationship between the disruption of mitochondrial metabolism during aging and cellular quiescence that underlies age-related decline in fertility and wound repair. Moving forward, correcting the metabolic defects in quiescent cells that occur during aging might provide a powerful platform to improve wound repair and the regenerative potential of tissue during aging. It also could provide a means to extend the window of fertility for women, reducing need for in vitro fertilization (IVF) for women wishing to conceive later in life.

Although cancer cells are typically considered highly proliferative, cellular quiescence can play a key role in cancer incidence and recurrence (Fig. 3). Tumors display a great deal of cellular heterogeneity that includes subpopulations of quiescent cells (Dagogo-Jack and Shaw, 2018; Turashvili and Brogi, 2017; Esparza-Lopez et al., 2017). The precise origin of these cells and why these subpopulations enter quiescence is not well understood. Their entry into quiescence is likely caused by stress in the tumor microenvironment and conventional cancer treatments, but this is mostly speculation. These quiescent cancer cells can respond to stimuli from the tumor microenvironment and reactivate by restoring metabolic activity and re-entering the cell cycle (Atashzar et al., 2020; Flavahan et al., 2017; Liu et al., 2022; Sun and Yang, 2019). One of the primary causes of the recurrent nature of many solid tumors are these sub-populations of quiescent cells (Bruttel and Wischhusen, 2014; Sosa et al., 2014). These cells are non-proliferative and display low metabolic activity (Zhao, 2016). Interestingly, most conventional therapies (radiation and chemotherapy) target highly proliferative cells by inducing DNA damage. As a result, being in this dormant state protects quiescent cancer cells from such approaches (Chen et al., 2016; Gasch et al., 2017; Zhao, 2016). Survival of these chemotherapy-resistant quiescent cancer cells allows them to later emerge from quiescence and seed new tumor growth (Chen et al., 2016; Gasch et al., 2017; Zhao, 2016).

Quiescent cancer cells can also escape the tissue of origin and metastasize to different tissues and give rise to secondary tumors (Goddard et al., 2018). Interestingly, quiescent tumor cells can remain dormant in tissues for up to 20 years before re-entering the cell cycle to begin metastatic expansion (Goddard et al., 2018). As a result, understanding the metabolic state of quiescent cancer cells provides a platform for the development of combinatorial therapies that reduce cancer recurrence and enhance patient outcomes (Aramini et al., 2022; Chen et al., 2016; Yang et al., 2020). Reactivation of these cancer cells is likely triggered by stress and changes in the metabolic state of the tumor microenvironment. Given metabolic changes can drive differentiation and growth (Flavahan et al., 2017), it is possible to utilize metabolic reprogramming to push quiescent cancer cells into a state where conventional therapies are more effective (Gasch et al., 2017; Morrison, 2022).

Cancer stem cells (CSCs) and differentiated cancer cells exhibit distinct metabolic states that are influenced by the tissue of origin and tumor microenvironment (Tanabe and Sahara, 2020; Yadav et al., 2020). CSCs engage in oxidative phosphorylation, whereas non-CSC cells favor aerobic glycolysis in cell culture studies of breast cancer (Chiche et al., 2010). Moreover, cancer cells and the cells in the microenvironment are proposed to communicate, in part, through bidirectional metabolic flux (Schiliro and Firestein, 2021). However, many of these studies rely of cell culture systems that might not reflect the physiology of a tumor. This highlights the need to study the in vivo metabolic profile of quiescent cells in cancers that are known to show a high rate of recurrence. Moreover, it remains unclear how the metabolic state of quiescent CSCs contributes to cancer due to their ability to evade treatment and promote tumor regrowth.

Several therapeutic strategies have been developed to manipulate cellular quiescence in tumor cells. Forcing cancer cells out of quiescence makes these cells more vulnerable to radiation and chemotherapy (Aramini et al., 2022; Chen et al., 2016). Pathways involved with quiescence entry and exit, such as Notch signaling and Wnt/β-catenin signaling, have been targeted in pharmacological studies to treat cancer and prevent recurrence (Zhang and Wang, 2020). However, these treatments have severe side effects due to roles of these pathways in stem cell regulation, wound repair, fertility and the immune response, making them less than ideal methods for patient treatment (Ryeom, 2011; Kahn, 2014). An alternative approach is to devise strategies that permanently prevent the activation of quiescent cancer cells entirely and prevent tumor growth (Aramini et al., 2022; Chen et al., 2016). Another method would be to use metabolomic rate to predict metabolic disruptions in cancer cells, providing a selective means to target quiescent cancer cells. By utilizing these strategies, it might be possible to develop medications that target the metabolic state of quiescent cancer cells and enhance the efficacy of conventional treatments as a combinatorial approach to reduce the risk of cancer recurrence.

Overall, in examining the metabolic aspects of cellular quiescence, we find mitochondrial metabolism is a central player in the quiescent state. Although there is a common suppression of mitochondrial respiration, the metabolic profile of quiescent cells can vary based on their level of dormancy. Quiescence can be developmentally regulated or induced by nutrient stress, leading to distinct physiological states. Although quiescence is a normal physiological process, it can be corrupted in diseases such as cancer and provides a means to evade conventional cancer therapies. As a result, targeting the metabolic state of quiescent cancer stem cells is a platform to prevent the recurrent nature of many cancers.

Moving forward, there are many outstanding questions surrounding the relationship between quiescence and metabolism. First, given that isolating adult stem cells causes quiescent stem cells to exit quiescence, new approaches need to be developed to confirm and extend our current understanding of the physiology of quiescent cells in vivo. The development of in vivo metabolite responsive reporters (Cambronne et al., 2016; Ellis and Wolfgang, 2012) can be used to monitor specific aspects of metabolism as cells transition in and out of quiescence. Second, although suppressing ROS is a key feature of quiescence, reducing mitochondrial function also has broad effects on nicotinamide adenine dinucleotide (NAD) redox balance, nucleotide biosynthesis, amino acid biosynthesis and fatty acid metabolism (Hocaoglu et al., 2021). These metabolic pathways might play key roles in controlling stemness and pluripotency in quiescent adult stem cell and oocytes. As a result, many questions remain about how these pathways support the quiescent state and ensure developmental competence of quiescent cells. Finally, it remains unclear how the reprogramming of the metabolic state that occurs during quiescence is coupled to the concomitant global shifts in transcription and proteostasis. Further examination of the metabolic aspects of quiescence provides a platform to protect quiescent cells and prevent the age-associated decline in fertility and wound repair seen in all systems.

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