Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Sep 1.
Published in final edited form as: Ageing Res Rev. 2014 Dec 31;23(0 0):67–74. doi: 10.1016/j.arr.2014.12.007

Mitochondria to Nucleus Signaling and the Role of Ceramide in Its Integration into the Suite of Cell Quality Control Processes during Aging Mitochondria to Nucleus Signaling and the Role of Ceramide in Its Integration into the Suite of Cell Quality Control Processes during Aging

S Michal Jazwinski 1
PMCID: PMC4480153  NIHMSID: NIHMS658133  PMID: 25555678

Abstract

Mitochondria to nucleus signaling has been the most extensively studied mode of inter-organelle communication. The first signaling pathway in this category of information transfer to be discovered was the retrograde response, with its own set of signal transduction proteins. The finding that this pathway compensates for mitochondrial dysfunction to extend the replicative lifespan of yeast cells has generated additional impetus for its study. This research has demonstrated crosstalk between the retrograde response and the target of rapamycin (TOR), small GTPase RAS, and high-osmolarity glycerol (HOG) pathways in yeast, all of which are key players in replicative lifespan. More recently, the retrograde response has been implicated in the diauxic shift and survival in stationary phase, extending its operation to the yeast chronological lifespan as well. In this capacity, the retrograde response may cooperate with other, related mitochondria to nucleus signaling pathways. Counterparts of the retrograde response are found in the roundworm, the fruit fly, the mouse, and even in human cells in tissue culture. The exciting realization that the retrograde response is embedded in the network of cellular quality control processes has emerged over the past few years. Most strikingly, it is closely integrated with autophagy and the selective brand of this quality control process, mitophagy. This coordination depends on TOR, and it engages ceramide/sphingolipid signaling. The yeast LAG1 ceramide synthase gene was the first longevity gene cloned as such, and its orthologs hyl-1 and hyl-2 determine worm lifespan. Thus, the involvement of ceramide signaling in quality control gives these findings cellular context. The retrograde response and ceramide are essential components of a lifespan maintenance process that likely evolved as a cytoprotective mechanism to defend the organism from diverse stressors.

Key terms: Saccharomyces cerevisiae, Caenorhabditis elegans, Lifespan, Sphingolipids, Retrograde response, Autophagy

1. Introduction

Cellular quality control has emerged as a central player in aging. This is not only the case in terms of resistance to age-related diseases, but also to longevity itself, at least in lower organisms. This issue of the journal reviews many aspects of these relationships, while considering various quality control mechanisms at the cell’s disposal. It may not be as easy to discern, however, how all of these devices are integrated to provide a suite of mechanisms that tailor the response to the situation the cell encounters.

This article provides an overview of a compensatory response the cell deploys when it is faced with mitochondrial dysfunction. Rather than eliminating the source of the dysfunction, this response makes the best of a bad situation by adapting cell physiology to the worsening state of affairs. Thus, one could consider this to be a last ditch effort at survival. Surprisingly, the cell (and organism) appears to thrive under these new circumstances, and it can live longer. This certainly surmounts any limitations of quality control mechanisms, and, indeed, it complements them nicely.

The view just presented would neglect an important feature of the compensatory response to mitochondrial dysfunction. This is its firm coordination with other cell quality control mechanisms. It is this aspect that draws our attention in this article. However, there are two additional issues that will be discussed. The first concerns the nature of the underlying coordination and the signals that are involved. The second, and perhaps related question, that will be touched upon briefly is the evolution of the compensatory response.

2. The yeast retrograde response

The compensatory response alluded to above is the retrograde response, first identified in yeast as retrograde signaling to denote a mechanism of communication from the mitochondrion to the nucleus (Butow and Avadhani, 2004). Subsequently, the moniker “retrograde response” was bestowed, as its broad impact on cell physiology became clear (Jazwinski, 1999). Activation of the retrograde response due to mitochondrial dysfunction, which can be induced in various ways, results in changes in the expression of some 400 nuclear genes (Epstein, et al., 2001, Traven, et al., 2001). CIT2, encoding peroxisomal citrate synthase, is one of these genes, and its induction is often used as a robust indicator of retrograde response activation (Liao, et al., 1991). The gene expression changes that encompass the retrograde response adjust cell metabolism to life without a fully functioning Krebs cycle. This is achieved through the activation of anaplerotic reactions and the conservation of carbon in the peroxisomal glyoxylate cycle, among others. Furthermore, pathways that enhance the ability to resist stress are induced, including xenobiotic stress.

Retrograde signaling consists of a bona fide, intracellular signaling pathway. A signal elicited by dysfunctional mitochondria is transduced by the Rtg2 protein, resulting in the translocation of the Rtg1-Rtg3 transcription factor from the cytoplasm to the nucleus. This deceptively uncomplicated set of events involves the interactions of several proteins, which will not be presented here. Similarly, the connection of retrograde signaling to epigenetic gene regulation and genomic stability will not be examined. These details have been thoroughly discussed recently (Jazwinski, 2012a, Jazwinski, 2012b, Jazwinski, 2014, Jazwinski and Kriete, 2012, Srinivasan, et al., 2010).

The nature of the mitochondrial signal that triggers the retrograde response deserves some comment, as it had been an enigma until recently. Fundamentally, there could be three signals emanating from dysfunctional mitochondria. One are reactive oxygen species (ROS); another is a drop in ATP levels; and, the third is a reduction in mitochondrial membrane potential. The third of these alternative signals has been shown to be the elusive, physiologic signal in dividing cells, while ROS were excluded (Miceli, et al., 2011). Recently, it has been shown that Rtg2 protein is released from the Mks1 protein, an inhibitor of retrograde signaling, in the presence of ATP (Zhang, et al., 2013). This reaction was demonstrated in vitro. Mks1 can then prevent the partial dephosphorylation of Rtg3 protein and the consequent translocation of Rtg1-Rtg3 to the nucleus. It can be argued that ATP levels fall in the cell when oxidative phosphorylation is blocked, and the cell generates ATP through fermentation. Interestingly, fermenting yeast cells grow faster than respiring ones. Furthermore, further taxing ATP pools in fermenting cells to reverse the decline in mitochondrial membrane potential actually suppresses retrograde signaling in living yeast cells (Miceli, et al., 2011). These facts would argue against the notion of a drop in ATP as the mitochondrial signal of the retrograde response. However, there is the possibility that a localized pool of ATP is involved in vivo, and that its reduction could act in tandem with the drop in mitochondrial membrane potential.

3. Crosstalk of retrograde signaling with other signaling pathways

There are three major signaling pathways with which retrograde signaling interacts. These are the target of rapamycin (TOR), the small GTPase RAS, and the high-osmolarity stressresponsive kinase HOG pathways (Fig. 1).

Figure 1.

Figure 1

Open in a new tab

Crosstalk of retrograde signaling with other signaling pathways. Availability of nutrients activates TORC1, which inhibits retrograde signaling and activates Sch9. This activation of Sch9 is inhibited by the retrograde response. The protein kinase Sch9 activates ribosome biogenesis, while inhibiting protein kinase A and the Msn2-Msn4 transcription factor, which is responsible for activating stress response genes. Protein kinase A also inhibits this transcription factor while stimulating ribosome production. Protein kinase A feedback inhibits its own activation. One or more signals activate Ras2, which functions in a cAMP-dependent and a cAMP-independent pathway. The first of these is likely to block the retrograde response, as it is known to curtail RLS, which is maintained by progressive activation of the retrograde response during the RLS. The second pathway is known to extend the RLS, and Ras2 is required for the retrograde response that extends RLS. The Hog1 protein kinase is responsive to osmotic stress and to hypoxia. It activates the retrograde response directly and by inhibiting TORC1. Activation of the retrograde response extends lifespan.

TOR complex 1 (TORC1) negatively regulates retrograde signaling, acting both upstream and downstream of Rtg2 (Breitkreutz, et al., 2010, Giannattasio, et al., 2005, Komeili, et al., 2000). TOR is a sensor of nutrient status in the cell. Glutamate availability activates TORC1 signaling, and its downstream outcomes such as ribosome biogenesis. The retrograde response is repressed by glutamate, and mutants in the RTG genes are glutamate auxotrophs (Jia, et al., 1997, Liao and Butow, 1993, Liu and Butow, 2006). Lst8, a component of TORC1, was shown to be a negative regulator of retrograde signaling in genetic studies, acting both upstream and downstream of Rtg2 (Roberg, et al., 1997). Those mutants of LST8 which act upstream of Rtg2 resemble phenotypically mutations in a plasma membrane amino acid sensor.

TORC1 phosphorylates the AGC protein kinase Sch9, and this is markedly reduced in cells in which retrograde signaling activity occurs (Kawai, et al., 2011). This has important consequences, as phosphorylation of Sch9 inhibits the activation of stress responses dependent on the Msn2-Msn4 transcription factor, while activating ribosome biogenesis (Urban, et al., 2007). Thus, stress responses would be elevated with concomitant decline in ribosome production in the retrograde response. Phosphorylation of Sch9 also inhibits cAMP-dependent, protein kinase A activity, which facilitates the activation of Msn2-Msn4 mediated stress responses (Zhang, et al., 2011). Inhibition of protein kinase A would result in the inhibition of growth in the presence of nutrients. This does not happen, however, because protein kinase A feedback inhibits this effect of Sch9. The net effect of this feedback loop on inhibition of TORC1 in cells possessing dysfunctional mitochondria is to balance cell growth and metabolism with stress responses.

Ras2 is required for the retrograde response (Kirchman, et al., 1999). Mks1, the negative regulator of retrograde signaling, was first identified as a negative regulator of Ras2-cAMP signaling, which might implicate Ras2-cAMP in the crosstalk with retrograde signaling. However, a Ras2 pathway that is cAMP-independent has also been described (Mosch, et al., 1996, Sun, et al., 1994), and it could be this pathway that is relevant (see below). The downstream target of the Ras2-cAMP pathway is protein kinase A, which ties together retrograde signaling, TORC1, and Ras2 signaling.

The hyperosmolarity-activated, Hog1 protein kinase pathway regulates the Rtg1-Rtg3 transcription factor (Ruiz-Roig, et al., 2012). Translocation of Rtg1-Rtg3 into the nucleus requires Hog1, as does the binding of this transcription factor to chromatin and transactivation of gene expression. Interestingly, the osmotic stress that activates Hog1 also results in a transient reduction in Sch9 phosphorylation by TORC1 (Urban, et al., 2007). This would serve to upregulate, transiently, a plethora of cellular stress responses, while slowing ribosome production and growth. Clearly, the activities of the retrograde signaling pathway, TORC1, Ras2, and Hog1 communicate and are closely coordinated.

4. The retrograde response affects yeast lifespan

The significance of the retrograde response in aging first became apparent when it was demonstrated that the activation of the retrograde signaling pathway extended the yeast replicative lifespan (RLS) (Kirchman, et al., 1999). The RLS is defined by the number of times an individual yeast cell divides, or in other words the number of daughter cells produced. Subsequently, it was shown that activation of this pathway is necessary for the extension of chronological lifespan (CLS) (Barros, et al., 2004), which is the time yeast cells survive in a non-dividing, stationary phase that is usually measured in the absence of nutrients.

The retrograde response is not the only pathway connecting RLS and CLS. TORC1 signaling, as an expression of intracellular nutrient status, does so as well. This is amply demonstrated by the fact that deletion of SCH9, which encodes a protein kinase that is an effector of TORC1, extends both RLS and CLS (Fabrizio, et al., 2001, Kaeberlein, et al., 2005). This is curious because of the markedly different growth status of cells under the two conditions. Yeast cells in stationary phase respire, albeit slowly. This is connected to ROS generation, and stationary phase cells launch antioxidant defenses to account for it (Piper, 2012). They must do this sufficiently. Dividing cells can “runaway” from damage, in essence leaving damage behind as clones expand exponentially. This is particularly feasible due to age asymmetry in the segregation of damaged and dysfunctional constituents (Jazwinski, 2012a). The resolution of the paradoxical effect of SCH9 deletion on both RLS and CLS may reside in the balance struck by the feedback loop that connects TORC1 and Ras2 signaling through Sch9 and protein kinase A, discussed earlier.

Deletion of RAS2 curtails RLS (Sun, et al., 1994), but it extends CLS (Fabrizio, et al., 2003). Significantly, it is the cAMP-independent pathway that is involved in the former and the cAMPdependent protein kinase A pathway in the latter. These effects highlight the differences between RLS and CLS mentioned above, and they also point to the critical nature of the feedback loop just discussed. It appears that there is a trade-off that allows cells to proliferate when nutrients are available (RLS) and to survive in their absence (CLS) that represent opposite ends of the functional spectrum afforded by this feedback loop. Absence of Ras2 makes stationary phase survival efficient. However, it compromises the ability to rapidly proliferate. Overexpression of RAS2 extends the RLS (Sun, et al., 1994), a situation that makes stationary phase arrest difficult. However, this RLS extension engages a Ras2 cAMP-independent pathway; activation of the cAMP-dependent pathway curtails RLS (Sun, et al., 1994).

In the discussion of the mitochondrial signal that triggers the retrograde response, one possible signal that was mentioned was ROS. The retrograde response in yeast cells dividing during the RLS does not involve ROS signaling (Miceli, et al., 2011). However, ROS signaling from the mitochondrion to the nucleus is involved in CLS extension in non-dividing cells, and this requires TORC1 (Pan, et al., 2011). It should be pointed out that such cells do not necessarily contain dysfunctional mitochondria, and they not only generate ROS but also upregulate ROS defenses, which may be among the many ROS-dependent, epigenetic changes in gene expression. Although mitochondrial dysfunction increases during the RLS (Lai, et al., 2002, Laun, et al., 2001), this is not necessarily equivalent to the drastic effects on mitochondrial function that are used to elicit the retrograde response experimentally (Borghouts, et al., 2004). Indeed, even modest decreases in mitochondrial membrane potential can activate the retrograde response and increase RLS (Jazwinski, 2000, Miceli, et al., 2011).

5. Retrograde response in other organisms

Certain metabolic changes that occur during aging in Caenorhabditis elegans resemble those that are found in yeast on retrograde response activation, which led to the proposal that there is an operative retrograde response in this round worm (Kirchman, et al., 1999). In fact, there appear to be three such pathways. One of them involves the hypoxia-inducible transcription factor HIF-1, which is activated by mitochondrial ROS (Lee, et al., 2010). Another engages the mitochondrial unfolded protein response and the transcription factors UBL-5 and DVE-1 (Durieux, et al., 2011), while the third is mediated by the predicted homeobox transcription factor CEH-23 (Walter, et al., 2011). The phenotypes associated with the lifespan extension afforded by mitochondrial dysfunction in the worm can be varied (Yang and Hekimi, 2010), and they can incorporate hormonal effects by bile acid-related species (Liu, et al., 2012). Similar to the worm studies, knockdown of respiratory chain components in Drosophila also extends lifespan (Copeland, et al., 2009), as does defective coenzyme Q synthesis (Liu, et al., 2011), but the signaling pathways are not known.

Mouse lifespan has also been extended by disruption of mitochondrial function in several ways. Lowered coenzyme Q synthesis through reduced activity of the MLCK1 gene is associated with increased longevity (Lapointe and Hekimi, 2008). This appears to be the result of a subtle effect on the balance of ROS production in the mitochondrion and in the cytoplasm. The model explaining these effects of lowered coenzyme Q synthesis proposes reduced cytoplasmic ROS production coupled to enhanced antioxidant defenses. The latter could be linked to mitochondria-generated ROS signaling gene expression changes in the nucleus. A SURF1 conditional knockout, which interferes with cytochrome oxidase assembly also extends mouse lifespan (Dell'agnello, et al., 2007). Surprisingly, even a complete lack of the Surf1 cytochrome oxidase assembly factor was compatible with postnatal survival. Importantly, mild mitochondrial uncoupling produced by feeding dinitrophenol to mice not only extends lifespan, but it also improves a variety of metabolic parameters, including serum glucose, triglyceride and insulin levels (Caldeira da Silva, et al., 2008). In similarity, normal, diploid human fibroblasts show an increase in population doubling levels when supplied with dinitrophenol in the medium, while ROS are suppressed, telomere shortening is reduced, and DNA repair foci are sparse (Passos, et al., 2007).

6. Integration of the retrograde response into the cell quality control suite and ceramide

The retrograde response is firmly embedded in the cell quality control network. This is so much the case that it is virtually impossible to completely discuss this topic in a short review. There are three elements of quality control which will be touched upon here (Fig. 2). The first concerns the removal of damaged or excess proteins of the mitochondrial inner membrane with the assistance of the prohibitins, Phb1 and Phb2. The second involves removal of damaged or dysfunctional mitochondria through autophagy, which can be selective for this organelle (mitophagy). The third process depends on asymmetric segregation of damaged or dysfunctional mitochondria. These three processes will be discussed in order.

Figure 2.

Figure 2

Open in a new tab

Integration of the retrograde response into the cell quality control network. The retrograde response activates prohibitin gene expression, promoting degradation of supernumerary and damaged mitochondrial inner membrane proteins. The retrograde response also activates expression of the ceramide synthase gene LAC1, whose product, ceramide, is a substrate for the synthesis of complex sphingolipids that inhibit general autophagy. This synthesis is mediated by Ipt1 and Skn1. Ceramide can block authophagy on its own, and it activates the Sit4-containing protein phosphatase 2A which has the same effect. This protein phosphatase is also activated by TORC1. Ceramide can also inhibit Hog1 protein kinase. Complex sphingolipids are also a source of ceramide when they are liberated by Isc1 after it translocates to the mitochondrion. Ceramide synthase is activated by TORC2 via the protein kinase Ypk2. Ceramide synthase is inhibited by the protein phosphatase calcineurin. TORC1 blocks the retrograde response. It also activates protein kinase Sch9, which is both an effector and a regulator of sphingolipid metabolism. TORC1 phosphorylates Atg13 in the Atg1-Atg13 complex that is essential for autophagy. Protein kinase A phosphorylates both of these proteins to block autophagy, and it also inhibits the retrograde response. The retrograde response stimulates stationary phase mitophagy with the participation of the Aup1 protein phosphatase. Hog1 plays an essential role in this process. The retrograde response also induces multi-drug resistance transporters, such as Pdr5, in the plasma membrane. I speculate that the retrograde response may also impinge upon age asymmetry in the segregation of damaged or dysfunctional mitochondria, either directly or through ceramide signaling.

Expression of PHB1 and PHB2 is activated in the retrograde response (Traven, et al., 2001). The products of these genes perform a chaperone function in the assembly of mitochondrial inner-membrane protein complexes (Nijtmans, et al., 2000), and it has been suggested that prohibitins deliver excess mitochondrial membrane proteins to the inner membrane m-AAA protease for degradation (Kirchman, et al., 2003). Deletion of either or both of the prohibitin genes severely curtails RLS of rho0 cells (Kirchman, et al., 2003). Mitochondrial DNA (mtDNA) is missing in rho0 cells, which results in the lack of production of mtDNA-encoded components of the electron transport chain, and this defect activates the retrograde response which in some yeast strains is glucose-repressed (Kirchman, et al., 1999). Importantly, deletion of RAS2 completely suppresses the RLS deficit of rho0 cells in which prohibitin genes are deleted (Kirchman, et al., 2003).

Ras2 stimulates the synthesis of nuclear-encoded components of the mitochondrial respiratory chain (Dejean, et al., 2002, Kirchman, et al., 2003). Thus, deletion of RAS2 would reduce the imbalance between the respiratory chain proteins synthesized in the cytoplasm and in the mitochondrion that occurs in rho0 cells lacking prohibitins. The phenotypic consequences of a prohibitin deficit in rho0 cells is also suppressed by deletion of TOR1 or SCH9 (Wang, et al., 2008). Elimination of the TORC1/Sch9 pathway depresses mitochondrial biogenesis, as mentioned earlier.

The second aspect of cell quality control relevant to our discussion is autophagy, and particularly selective autophagy in the form of mitophagy. Autophagy is a genetically-orchestrated process by which various cytoplasmic components are delivered to the lysosome, in yeast called the vacuole, for degradation. Whole organelles can be disposed of in this way, and in mitophagy these are the mitochondria. Autophagy can generate building blocks for biosynthesis, particularly in times of scarcity. However, it also removes damaged cell components, acting as a quality control mechanism. Autophagy and mitophagy would be deleterious to the cell if not balanced by relevant biosynthetic reactions and organelle biogenesis. It is not clear how this balance operates in detail in yeast. However, yeast cells attempt to compensate for accumulation of dysfunctional mitochondria during the replicative lifespan, though the mitochondrial biogenesis that occurs cannot keep up (Lai, et al., 2002). In mammalian skeletal muscle, there is a decline in mitochondrial biogenesis with age, coupled to a reduction in mitochondrial dynamics (fission/fusion) and mitophagy (Chistiakov, et al., 2014)

The retrograde response and autophagy have crosstalk with TORC1 in common. Inhibition of TORC1 triggers autophagy, sensed by the cell as a state of starvation. TORC1 blocks autophagy by phosphorylating Atg13, which is part of the Atg1 protein kinase complex that is essential for autophagy (Kamada, et al., 2010). Nitrogen starvation induces autophagy in yeast, and this is further stimulated by deletion of IPT1 and SKN1 (Thevissen, et al., 2010). The products of these two genes are involved in the synthesis of yeast sphingolipids, the manosyldi-inositol phosphorylceramides. Thus, these molecules act as signals modulating the extent of autophagy. Autophagy is also inhibited by c-AMP-dependent, protein kinase A phosphorylation of both Atg1 and Atg13 (Stephan, et al., 2009). This is distinct from the regulation by TORC1, which targets different sites for phosphorylation on Atg13.

Like TORC1, TORC2 also has an AGC protein kinase as its target, Ypk2 (Aronova, et al., 2008). In this way, TORC2 regulates the activity of ceramide synthase, an enzyme essential for synthesis of the signaling molecule ceramide and all sphingolipids, which are derived from it. Ceramide synthase activity is thus stimulated in the presence of nutrients, which would attenuate autophagy. Cellular stress inhibits ceramide synthase activity, in contrast. This inhibition is mediated by the calcium/calmodulin-dependent protein phosphatase calcineurin. In this fashion, stress would enhance autophagy. In sum, both TORC1 and TORC2 regulate autophagy, and ceramide plays a role in this process.

In yeast, there are two homologous genes that encode ceramide synthase activity, LAG1 and LAC1 (Guillas, et al., 2001, Jiang, et al., 1998, Schorling, et al., 2001). LAG1 was the first gene cloned as a longevity assurance gene (D'Mello N, et al., 1994, Jiang, et al., 1998). The human orthologs encode six ceramide synthases Lass1-6 (Guillas, et al., 2003, Teufel, et al., 2009, Venkataraman, et al., 2002). Interestingly, LAC1 expression is regulated coordinately with the multi-drug resistance membrane transporter gene PDR5, which along with other members of this gene family is activated in the retrograde response (Hallstrom and Moye-Rowley, 2000, Kolaczkowski, et al., 2004, Moye-Rowley, 2005). It would seem that ceramide synthase activity must be finely tuned. This certainly is the case when RLS extension by LAG1 expression is concerned (Jiang, et al., 2004).

Deletion of CRD1, which encodes cardiolipin synthase, leads to delay of cell division in rho0 cells (Chen, et al., 2010, Vaena de Avalos, et al., 2005). The cause is the up-regulation of synthesis of the morphogenesis checkpoint protein Swe1, which requires activation of retrograde signaling. During diauxic shift, Isc1 translocates from the cytoplasm to the mitochondrial membrane where it exhibits cardiolipin-dependent inositol sphingolipid phospholipase C activity (Vaena de Avalos, et al., 2004). This results in production of ceramide, which activates a pathway parallel to retrograde signaling that is responsible for induction of a wide array of genes necessary for adaptation to stationary phase (Kitagaki, et al., 2009). The protein phosphatase 2A (PP2A), whose catalytic subunit is Sit4 protein is regulated by Isc1 (Barbosa, et al., 2011). Ceramide activates PP2A. This could well be the parallel pathway referred to here. PP2A, just like the retrograde response, is regulated by TORC1. Furthermore, inactivation of Sit4 stimulates autophagy, and this effect occurs downstream of TORC1 (Yorimitsu, et al., 2009). Ceramide arrests cells in the G1 phase of the cell cycle by activating PP2A (Nickels and Broach, 1996). The ISC1 and SWE1 genes interact (Tripathi, et al., 2011). Thus, the retrograde response regulates expression of SWE1, while ceramide may regulate the activity of Swe1 protein. The deletion of SIT4 in rho0 cells suppresses defects in mitochondrial protein import, cell proliferation, loss of mitochondrial membrane potential, autophagy deficit, and retrograde signaling (Garipler, et al., 2014). On the other hand, deletion of SIT4 in isc1Δ cells rescues their premature chronological aging and oxidative stress sensitivity (Barbosa, et al., 2011). Deletion of TOR1 or SCH9 in cells devoid of ISC1 suppresses mitochondrial dysfunction, sensitivity to oxidative stress, and curtailed CLS (Teixeira, et al., 2014), further distinguishing dividing from non-dividing cells. Hog1 hyperphosphorylation is required for the effect of SCH9 deletion but not for TOR1 deletion. The mutual relationship of the TORC1-Sch9 signaling pathway and ceramide signaling is indeed complex. Sch9 regulates stress tolerance and longevity in yeast by acting as both an effector and a regulator of sphingolipid metabolism (Swinnen, et al., 2014).

Inhibition of the de novo sphingolipid synthesis pathway activates the HOG pathway at the level of the osmosensing machinery (Tanigawa, et al., 2012). Interestingly, Hog1 has recently been shown to be activated by hypoxia, in a manner and with consequences distinct from its activation by osmotic stress (Hickman, et al., 2011). Deletion of ISC1 leads to activation of Hog1, and it also activates the cell wall integrity pathway in yeast (Barbosa, et al., 2012), which plays a role in RLS (Kaeberlein and Guarente, 2002) as well as CLS.

Atg32 tags mitochondria for selective removal in the process of mitophagy (Kanki and Klionsky, 2009, Kanki, et al., 2009a, Kanki, et al., 2009b, Okamoto, et al., 2009a, Okamoto, et al., 2009b). Mitophagy in stationary phase requires retrograde signaling (Journo, et al., 2009). The Aup1 protein phosphatase, which is located in the mitochondrial intermembrane space, is essential. Deletion of AUP1 blocks retrograde signaling, and deletion of RTG3 prevents mitophagy. Not surprisingly, the phosphorylation pattern on Rtg3 depends on Aup1. In addition to this connection to retrograde signaling, crosstalk with Hog1 is also involved. The Hog1 protein kinase functions specifically in mitophagy (Mao, et al., 2011).

The third issue related to quality control is the age asymmetry in segregation of mitochondria during cell division. During cell division, approximately equal amounts of mitochondrial material find their way into the mother and its daughter (Simon, et al., 1997). As the mother cell becomes older during the RLS, its mitochondria suffer damage and dysfunction, judging by many different parameters (Kirchman, et al., 2003, Klinger, et al., 2010, Lai, et al., 2002, Lam, et al., 2011, Laun, et al., 2001, McFaline-Figueroa, et al., 2011, Piper, et al., 2002, Seo, et al., 2007). These dysfunctional mitochondria are retained by mother cells (Lai, et al., 2002, McFaline- Figueroa, et al., 2011, Piper, et al., 2002). This age asymmetry is reflected in the fact that daughter cells have before them the prospects of a full RLS. However, this age symmetry breaks down as mother cells age (Egilmez and Jazwinski, 1989, Kennedy, et al., 1994). Structural and functional asymmetry is the basis for a theory of aging (Jazwinski, 1993). Mutants in age asymmetry have been isolated in which daughters are born old, revealing that at least one of its sources is the segregation of dysfunctional mitochondria to the mother (Lai, et al., 2002). It will be of interest to determine how this might tie in to the retrograde response which is activated by mitochondrial dysfunction.

It is important to note here that other sorts of damaging agents also display age asymmetry in their segregation. They include extrachromosomal rDNA circles (Sinclair and Guarente, 1997) and aggregated and oxidized proteins (Aguilaniu, et al., 2003, Liu, et al., 2010).

7. Retrograde signaling is a response to cytotoxic stress

Longevity regulation has recently been proposed to have evolved from cytoprotective pathways responsive to diverse triggers across species (Shore and Ruvkun, 2013). The C. elegans retrograde response was the primary consideration in this proposal. Among the stressors discussed were xenobiotics and pathogens that have plagued cells and organisms since early in evolution. The important point was that resistance to one specific stressor induced crossprotection to other stressors, which is typical of hormesis. This resistance includes detoxification of xenobiotics and induction of autophagy. On point, exposure to any stressor induces a common set of responses that protect against various stressors, repair the damage, or remove the defective cellular structures. As it happens, these are the same structures that are susceptible to damage during aging. According to the model, it is the damage itself rather than the damaging agents that are sensed, making this a relatively parsimonious response.

Exposure of yeast to the xenobiotic erythromycin, an agent that blocks mitochondrial protein translation was determined long ago to extend RLS (Holbrook and Menninger, 2002). This is consistent with the cytoprotection model discussed above. Furthermore, activation of the retrograde response triggers the expression of PDR5 and other genes of the cytoplasmic-membrane localized multi-drug resistance transporter family that pump xenobiotics out of cells, and this occurs coordinately with expression of the ceramide synthase gene LAC1 (Hallstrom and Moye-Rowley, 2000, Kolaczkowski, et al., 2004, Moye-Rowley, 2005). This links mitochondrial dysfunction, whether it occurs during aging or through the action of external agents, to cross cross-protection against a panoply of xenobiotics, and it is associated with RLS and CLS extension, as discussed earlier.

Certain genotoxic agents can deplete nucleotide pools in the cell, which can result in DNA replication stress, and induction of RNR1, encoding ribonucleotide reductase, can rescue this situation (Weinberger, et al., 2013). DNA replication stress is known to curtail the RLS (Weinberger, et al., 2013). The retrograde response genes RTG1, RTG2, and RTG3 regulate a metabolic circuit that can buffer deficiencies in ribonucleotide reductase (Hartman, 2007). ISC1 interacts with DNA integrity checkpoint genes in yeast (Tripathi, et al., 2011), implicating ceramide signaling in the response to DNA replication stress. Indeed, Isc1 impacts both the DNA replication and DNA damage checkpoints in yeast. ISC1 appears to be synthetic with the replication checkpoint mediators MRC1, TOF1, and CSM3, with SWE1 downstream, and this is further connected to actin cytoskeleton dynamics. In parallel, ISC1 cooperates with the damage checkpoint gene RAD9, whose readout is mediated by RAD53 and its target CDK1. These two parallel checkpoint pathways may be interconnected. As mentioned earlier, the retrograde response regulates expression of SWE1, while ceramide may regulate the activity of Swe1 protein. The findings summarized here provide additional support for the role of ceramide and sphingolipids in cytoprotection in yeast and connects them to the retrograde response.

One of the C. elegans homologs of LAG1 is hyl-2 (Jiang, et al., 1998). The ceramide species synthesized by HYL-2 have a pro-survival effect. They are involved in the activation of HIF-1 (Menuz, et al., 2009) whose activity extends worm longevity (Mehta, et al., 2009). It is noteworthy that ROS generated by mitochondrial dysfunction in the C. elegans retrograde response extends lifespan in a hif-1-dependent manner (Lee, et al., 2010). Another worm LAG1 homolog is hyl-1 (Jiang, et al., 1998), and the ceramide generated by the ceramide synthase it encodes has pro-apoptotic effects (Menuz, et al., 2009). Knockdown of hyl-1 extends worm lifespan (Tedesco, et al., 2008). Recently, it has been shown that mitochondrial dysfunction in C. elegans extends lifespan by countering the classic apoptotic pathway (Yee, et al., 2014). This is the case even though the worm does not die due to wholesale apoptosis.

The critical role of ceramide and sphingolipids in longevity that was first found in the yeast Saccharomyces cerevisiae (D'Mello N, et al., 1994, Guillas, et al., 2001, Jiang, et al., 2004, Jiang, et al., 1998) has been highlighted recently in C. elegans (Liu, et al., 2014). A comparison of the genetic determinants of lifespan extension in the worm induced by various cytotoxic agents prominently featured ceramide and its metabolism. This is not surprising, as it is known that sphingolipids impact virtually every signaling pathway in the yeast cell that is relevant for longevity (Huang, et al., 2013, Liu, et al., 2013). This includes the various pathways and cellular processes with which the retrograde response cross-talks. Thus, ceramide is central to the integration of the retrograde response into the suite of cellular quality control that is crucial in aging and lifespan regulation.

Acknowledgments

The research in the author’s laboratory is supported by grant AG006168 from the National Institute on Aging of the National Institutes of Health (U.S.P.H.S.).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  1. Aguilaniu H, Gustafsson L, Rigoulet M, Nystrom T. Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science. 2003;299(5613):1751–1753. doi: 10.1126/science.1080418. [DOI] [PubMed] [Google Scholar]
  2. Aronova S, Wedaman K, Aronov PA, Fontes K, Ramos K, Hammock BD, Powers T. Regulation of ceramide biosynthesis by TOR complex 2. Cell Metab. 2008;7(2):148–158. doi: 10.1016/j.cmet.2007.11.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barbosa AD, Graca J, Mendes V, Chaves SR, Amorim MA, Mendes MV, Moradas-Ferreira P, Corte-Real M, Costa V. Activation of the Hog1p kinase in Isc1pdeficient yeast cells is associated with mitochondrial dysfunction, oxidative stress sensitivity and premature aging. Mech Ageing Dev. 2012;133(5):317–330. doi: 10.1016/j.mad.2012.03.007. [DOI] [PubMed] [Google Scholar]
  4. Barbosa AD, Osorio H, Sims KJ, Almeida T, Alves M, Bielawski J, Amorim MA, Moradas-Ferreira P, Hannun YA, Costa V. Role for Sit4p-dependent mitochondrial dysfunction in mediating the shortened chronological lifespan and oxidative stress sensitivity of Isc1p-deficient cells. Mol Microbiol. 2011;81(2):515–527. doi: 10.1111/j.1365-2958.2011.07714.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barros MH, Bandy B, Tahara EB, Kowaltowski AJ. Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae. J Biol Chem. 2004;279(48):49883–49888. doi: 10.1074/jbc.M408918200. [DOI] [PubMed] [Google Scholar]
  6. Borghouts C, Benguria A, Wawryn J, Jazwinski SM. Rtg2 protein links metabolism and genome stability in yeast longevity. Genetics. 2004;166(2):765–777. doi: 10.1534/genetics.166.2.765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Breitkreutz A, Choi H, Sharom JR, Boucher L, Neduva V, Larsen B, Lin ZY, Breitkreutz BJ, Stark C, Liu G, Ahn J, Dewar-Darch D, Reguly T, Tang X, Almeida R, Qin ZS, Pawson T, Gingras AC, Nesvizhskii AI, Tyers M. A global protein kinase and phosphatase interaction network in yeast. Science. 2010;328(5981):1043–1046. doi: 10.1126/science.1176495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Butow RA, Avadhani NG. Mitochondrial signaling: the retrograde response. Mol Cell. 2004;14(1):1–15. doi: 10.1016/s1097-2765(04)00179-0. [DOI] [PubMed] [Google Scholar]
  9. Caldeira da Silva CC, Cerqueira FM, Barbosa LF, Medeiros MH, Kowaltowski AJ. Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell. 2008;7(4):552–560. doi: 10.1111/j.1474-9726.2008.00407.x. [DOI] [PubMed] [Google Scholar]
  10. Chen S, Liu D, Finley RL, Jr, Greenberg ML. Loss of mitochondrial DNA in the yeast cardiolipin synthase crd1 mutant leads to up-regulation of the protein kinase Swe1p that regulates the G2/M transition. J Biol Chem. 2010;285(14):10397–10407. doi: 10.1074/jbc.M110.100784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chistiakov DA, Sobenin IA, Revin VV, Orekhov AN, Bobryshev YV. Mitochondrial aging and age-related dysfunction of mitochondria. BioMed research international. 2014;2014:238463. doi: 10.1155/2014/238463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Copeland JM, Cho J, Lo T, Jr, Hur JH, Bahadorani S, Arabyan T, Rabie J, Soh J, Walker DW. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr Biol. 2009;19(19):1591–1598. doi: 10.1016/j.cub.2009.08.016. [DOI] [PubMed] [Google Scholar]
  13. D'Mello NP, Childress AM, Franklin DS, Kale SP, Pinswasdi C, Jazwinski SM. Cloning and characterization of LAG1, a longevity-assurance gene in yeast. J Biol Chem. 1994;269(22):15451–15459. [PubMed] [Google Scholar]
  14. Dejean L, Beauvoit B, Bunoust O, Guerin B, Rigoulet M. Activation of Ras cascade increases the mitochondrial enzyme content of respiratory competent yeast. Biochem Biophys Res Commun. 2002;293(5):1383–1388. doi: 10.1016/S0006-291X(02)00391-1. [DOI] [PubMed] [Google Scholar]
  15. Dell'agnello C, Leo S, Agostino A, Szabadkai G, Tiveron C, Zulian A, Prelle A, Roubertoux P, Rizzuto R, Zeviani M. Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. Hum Mol Genet. 2007;16(4):431–444. doi: 10.1093/hmg/ddl477. [DOI] [PubMed] [Google Scholar]
  16. Durieux J, Wolff S, Dillin A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell. 2011;144(1):79–91. doi: 10.1016/j.cell.2010.12.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Egilmez NK, Jazwinski SM. Evidence for the involvement of a cytoplasmic factor in the aging of the yeast Saccharomyces cerevisiae. J Bacteriol. 1989;171(1):37–42. doi: 10.1128/jb.171.1.37-42.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Epstein CB, Waddle JA, Hale Wt, Dave V, Thornton J, Macatee TL, Garner HR, Butow RA. Genome-wide responses to mitochondrial dysfunction. Mol Biol Cell. 2001;12(2):297–308. doi: 10.1091/mbc.12.2.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Fabrizio P, Liou LL, Moy VN, Diaspro A, Valentine JS, Gralla EB, Longo VD. SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics. 2003;163(1):35–46. doi: 10.1093/genetics/163.1.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD. Regulation of longevity and stress resistance by Sch9 in yeast. Science. 2001;292(5515):288–290. doi: 10.1126/science.1059497. [DOI] [PubMed] [Google Scholar]
  21. Garipler G, Mutlu N, Lack NA, Dunn CD. Deletion of conserved protein phosphatases reverses defects associated with mitochondrial DNA damage in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2014;111(4):1473–1478. doi: 10.1073/pnas.1312399111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Giannattasio S, Liu Z, Thornton J, Butow RA. Retrograde response to mitochondrial dysfunction is separable from TOR1/2 regulation of retrograde gene expression. J Biol Chem. 2005;280(52):42528–42535. doi: 10.1074/jbc.M509187200. [DOI] [PubMed] [Google Scholar]
  23. Guillas I, Jiang JC, Vionnet C, Roubaty C, Uldry D, Chuard R, Wang J, Jazwinski SM, Conzelmann A. Human homologues of LAG1 reconstitute Acyl-CoAdependent ceramide synthesis in yeast. J Biol Chem. 2003;278(39):37083–37091. doi: 10.1074/jbc.M307554200. [DOI] [PubMed] [Google Scholar]
  24. Guillas I, Kirchman PA, Chuard R, Pfefferli M, Jiang JC, Jazwinski SM, Conzelmann A. C26-CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p. Embo J. 2001;20(11):2655–2665. doi: 10.1093/emboj/20.11.2655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hallstrom TC, Moye-Rowley WS. Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae. J Biol Chem. 2000;275(48):37347–37356. doi: 10.1074/jbc.M007338200. [DOI] [PubMed] [Google Scholar]
  26. Hartman JLt. Buffering of deoxyribonucleotide pool homeostasis by threonine metabolism. Proc Natl Acad Sci U S A. 2007;104(28):11700–11705. doi: 10.1073/pnas.0705212104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hickman MJ, Spatt D, Winston F. The Hog1 mitogen-activated protein kinase mediates a hypoxic response in Saccharomyces cerevisiae. Genetics. 2011;188(2):325–338. doi: 10.1534/genetics.111.128322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Holbrook MA, Menninger JR. Erythromycin slows aging of Saccharomyces cerevisiae. J Gerontol A Biol Sci Med Sci. 2002;57(1):B29–B36. doi: 10.1093/gerona/57.1.b29. [DOI] [PubMed] [Google Scholar]
  29. Huang X, Liu J, Withers BR, Samide AJ, Leggas M, Dickson RC. Reducing signs of aging and increasing lifespan by drug synergy. Aging Cell. 2013;12(4):652–660. doi: 10.1111/acel.12090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Jazwinski SM. The genetics of aging in the yeast Saccharomyces cerevisiae. Genetica. 1993;91(1–3):35–51. doi: 10.1007/BF01435986. [DOI] [PubMed] [Google Scholar]
  31. Jazwinski SM. Molecular mechanisms of yeast longevity. Trends Microbiol. 1999;7(6):247–252. doi: 10.1016/s0966-842x(99)01509-7. [DOI] [PubMed] [Google Scholar]
  32. Jazwinski SM. Metabolic control and gene dysregulation in yeast aging. Ann N Y Acad Sci. 2000;908:21–30. doi: 10.1111/j.1749-6632.2000.tb06632.x. [DOI] [PubMed] [Google Scholar]
  33. Jazwinski SM. The retrograde response: When mitochondrial quality control is not enough. Biochim Biophys Acta. 2012a doi: 10.1016/j.bbamcr.2012.02.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Jazwinski SM. The Retrograde ResponseRetrograde Response and Other Pathways of Interorganelle CommunicationInterorganelle Communication in Yeast Replicative Aging. Sub-cellular biochemistry. 2012b;57:79–100. doi: 10.1007/978-94-007-2561-4_4. [DOI] [PubMed] [Google Scholar]
  35. Jazwinski SM. The retrograde response: a conserved compensatory reaction to damage from within and from without. Progress in molecular biology and translational science. 2014;127:133–154. doi: 10.1016/B978-0-12-394625-6.00005-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Jazwinski SM, Kriete A. The yeast retrograde response as a model of intracellular signaling of mitochondrial dysfunction. Front Physiol. 2012;3:139. doi: 10.3389/fphys.2012.00139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Jia Y, Rothermel B, Thornton J, Butow RA. A basic helix-loop-helix-leucine zipper transcription complex in yeast functions in a signaling pathway from mitochondria to the nucleus. Mol Cell Biol. 1997;17(3):1110–1117. doi: 10.1128/mcb.17.3.1110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Jiang JC, Kirchman PA, Allen M, Jazwinski SM. Suppressor analysis points to the subtle role of the LAG1 ceramide synthase gene in determining yeast longevity. Exp Gerontol. 2004;39(7):999–1009. doi: 10.1016/j.exger.2004.03.026. [DOI] [PubMed] [Google Scholar]
  39. Jiang JC, Kirchman PA, Zagulski M, Hunt J, Jazwinski SM. Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human. Genome Res. 1998;8(12):1259–1272. doi: 10.1101/gr.8.12.1259. [DOI] [PubMed] [Google Scholar]
  40. Journo D, Mor A, Abeliovich H. Aup1-mediated regulation of Rtg3 during mitophagy. J Biol Chem. 2009;284(51):35885–35895. doi: 10.1074/jbc.M109.048140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kaeberlein M, Guarente L. Saccharomyces cerevisiae MPT5 and SSD1 function in parallel pathways to promote cell wall integrity. Genetics. 2002;160(1):83–95. doi: 10.1093/genetics/160.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kaeberlein M, Powers RW, 3rd, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005;310(5751):1193–1116. doi: 10.1126/science.1115535. [DOI] [PubMed] [Google Scholar]
  43. Kamada Y, Yoshino K, Kondo C, Kawamata T, Oshiro N, Yonezawa K, Ohsumi Y. Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol. 2010;30(4):1049–1058. doi: 10.1128/MCB.01344-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Kanki T, Klionsky DJ. Atg32 is a tag for mitochondria degradation in yeast. Autophagy. 2009;5(8):1201–1202. doi: 10.4161/auto.5.8.9747. [DOI] [PubMed] [Google Scholar]
  45. Kanki T, Wang K, Baba M, Bartholomew CR, Lynch-Day MA, Du Z, Geng J, Mao K, Yang Z, Yen WL, Klionsky DJ. A genomic screen for yeast mutants defective in selective mitochondria autophagy. Mol Biol Cell. 2009a;20(22):4730–4738. doi: 10.1091/mbc.E09-03-0225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Kanki T, Wang K, Cao Y, Baba M, Klionsky DJ. Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Developmental cell. 2009b;17(1):98–109. doi: 10.1016/j.devcel.2009.06.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Kawai S, Urban J, Piccolis M, Panchaud N, De Virgilio C, Loewith R. Mitochondrial genomic dysfunction causes dephosphorylation of Sch9 in the yeast Saccharomyces cerevisiae. Eukaryot Cell. 2011;10(10):1367–1369. doi: 10.1128/EC.05157-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Kennedy BK, Austriaco NR, Jr, Guarente L. Daughter cells of Saccharomyces cerevisiae from old mothers display a reduced life span. J Cell Biol. 1994;127(6 Pt 2):1985–1993. doi: 10.1083/jcb.127.6.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Kirchman PA, Kim S, Lai CY, Jazwinski SM. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics. 1999;152(1):179–190. doi: 10.1093/genetics/152.1.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Kirchman PA, Miceli MV, West RL, Jiang JC, Kim S, Jazwinski SM. Prohibitins and Ras2 protein cooperate in the maintenance of mitochondrial function during yeast aging. Acta Biochim Pol. 2003;50(4):1039–1056. [PubMed] [Google Scholar]
  51. Kitagaki H, Cowart LA, Matmati N, Montefusco D, Gandy J, de Avalos SV, Novgorodov SA, Zheng J, Obeid LM, Hannun YA. ISC1-dependent metabolic adaptation reveals an indispensable role for mitochondria in induction of nuclear genes during the diauxic shift in Saccharomyces cerevisiae. J Biol Chem. 2009;284(16):10818–10830. doi: 10.1074/jbc.M805029200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Klinger H, Rinnerthaler M, Lam YT, Laun P, Heeren G, Klocker A, Simon-Nobbe B, Dickinson JR, Dawes IW, Breitenbach M. Quantitation of (a)symmetric inheritance of functional and of oxidatively damaged mitochondrial aconitase in the cell division of old yeast mother cells. Exp Gerontol. 2010;45(7–8):533–542. doi: 10.1016/j.exger.2010.03.016. [DOI] [PubMed] [Google Scholar]
  53. Kolaczkowski M, Kolaczkowska A, Gaigg B, Schneiter R, Moye-Rowley WS. Differential regulation of ceramide synthase components LAC1 and LAG1 in Saccharomyces cerevisiae. Eukaryot Cell. 2004;3(4):880–892. doi: 10.1128/EC.3.4.880-892.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Komeili A, Wedaman KP, O'Shea EK, Powers T. Mechanism of metabolic control. Target of rapamycin signaling links nitrogen quality to the activity of the Rtg1 and Rtg3 transcription factors. J Cell Biol. 2000;151(4):863–878. doi: 10.1083/jcb.151.4.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Lai CY, Jaruga E, Borghouts C, Jazwinski SM. A mutation in the ATP2 gene abrogates the age asymmetry between mother and daughter cells of the yeast Saccharomyces cerevisiae. Genetics. 2002;162(1):73–87. doi: 10.1093/genetics/162.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Lam YT, Aung-Htut MT, Lim YL, Yang H, Dawes IW. Changes in reactive oxygen species begin early during replicative aging of Saccharomyces cerevisiae cells. Free Radic Biol Med. 2011;50(8):963–970. doi: 10.1016/j.freeradbiomed.2011.01.013. [DOI] [PubMed] [Google Scholar]
  57. Lapointe J, Hekimi S. Early mitochondrial dysfunction in long-lived Mclk1+/−- mice. J Biol Chem. 2008;283(38):26217–26227. doi: 10.1074/jbc.M803287200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Laun P, Pichova A, Madeo F, Fuchs J, Ellinger A, Kohlwein S, Dawes I, Frohlich KU, Breitenbach M. Aged mother cells of Saccharomyces cerevisiae show markers of oxidative stress and apoptosis. Mol Microbiol. 2001;39(5):1166–1173. [PubMed] [Google Scholar]
  59. Lee SJ, Hwang AB, Kenyon C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol. 2010;20(23):2131–2136. doi: 10.1016/j.cub.2010.10.057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Liao X, Butow RA. RTG1 and RTG2: two yeast genes required for a novel path of communication from mitochondria to the nucleus. Cell. 1993;72(1):61–71. doi: 10.1016/0092-8674(93)90050-z. [DOI] [PubMed] [Google Scholar]
  61. Liao XS, Small WC, Srere PA, Butow RA. Intramitochondrial functions regulate nonmitochondrial citrate synthase (CIT2) expression in Saccharomyces cerevisiae. Mol Cell Biol. 1991;11(1):38–46. doi: 10.1128/mcb.11.1.38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Liu B, Larsson L, Caballero A, Hao X, Oling D, Grantham J, Nystrom T. The polarisome is required for segregation and retrograde transport of protein aggregates. Cell. 2010;140(2):257–267. doi: 10.1016/j.cell.2009.12.031. [DOI] [PubMed] [Google Scholar]
  63. Liu J, Huang X, Withers BR, Blalock E, Liu K, Dickson RC. Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan. Aging Cell. 2013;12(5):833–841. doi: 10.1111/acel.12107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Liu J, Wu Q, He D, Ma T, Du L, Dui W, Guo X, Jiao R. Drosophila sbo regulates lifespan through its function in the synthesis of coenzyme Q in vivo. J Genet Genomics. 2011;38(6):225–234. doi: 10.1016/j.jgg.2011.05.002. [DOI] [PubMed] [Google Scholar]
  65. Liu JL, Desjardins D, Branicky R, Agellon LB, Hekimi S. Mitochondrial Oxidative Stress Alters a Pathway in Caenorhabditis elegans Strongly Resembling That of Bile Acid Biosynthesis and Secretion in Vertebrates. PLoS Genet. 2012;8(3):e1002553. doi: 10.1371/journal.pgen.1002553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Liu Y, Samuel BS, Breen PC, Ruvkun G. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature. 2014;508(7496):406–410. doi: 10.1038/nature13204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Liu Z, Butow RA. Mitochondrial retrograde signaling. Annu Rev Genet. 2006;40:159–185. doi: 10.1146/annurev.genet.40.110405.090613. [DOI] [PubMed] [Google Scholar]
  68. Mao K, Wang K, Zhao M, Xu T, Klionsky DJ. Two MAPK-signaling pathways are required for mitophagy in Saccharomyces cerevisiae. J Cell Biol. 2011;193(4):755–767. doi: 10.1083/jcb.201102092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. McFaline-Figueroa JR, Vevea J, Swayne TC, Zhou C, Liu C, Leung G, Boldogh IR, Pon LA. Mitochondrial quality control during inheritance is associated with lifespan and mother-daughter age asymmetry in budding yeast. Aging Cell. 2011;10(5):885–895. doi: 10.1111/j.1474-9726.2011.00731.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Mehta R, Steinkraus KA, Sutphin GL, Ramos FJ, Shamieh LS, Huh A, Davis C, Chandler-Brown D, Kaeberlein M. Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science. 2009;324(5931):1196–1198. doi: 10.1126/science.1173507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Menuz V, Howell KS, Gentina S, Epstein S, Riezman I, Fornallaz-Mulhauser M, Hengartner MO, Gomez M, Riezman H, Martinou JC. Protection of C. elegans from anoxia by HYL-2 ceramide synthase. Science. 2009;324(5925):381–384. doi: 10.1126/science.1168532. [DOI] [PubMed] [Google Scholar]
  72. Miceli MV, Jiang JC, Tiwari A, Rodriguez-Quinones JF, Jazwinski SM. Loss of mitochondrial membrane potential triggers the retrograde response extending yeast replicative lifespan. Front Genet. 2011;2:102. doi: 10.3389/fgene.2011.00102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Mosch HU, Roberts RL, Fink GR. Ras2 signals via the Cdc42/Ste20/mitogenactivated protein kinase module to induce filamentous growth in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1996;93(11):5352–5356. doi: 10.1073/pnas.93.11.5352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Moye-Rowley WS. Retrograde regulation of multidrug resistance in Saccharomyces cerevisiae. Gene. 2005;354:15–21. doi: 10.1016/j.gene.2005.03.019. [DOI] [PubMed] [Google Scholar]
  75. Nickels JT, Broach JR. A ceramide-activated protein phosphatase mediates ceramideinduced G1 arrest of Saccharomyces cerevisiae. Genes Dev. 1996;10(4):382–394. doi: 10.1101/gad.10.4.382. [DOI] [PubMed] [Google Scholar]
  76. Nijtmans LG, de Jong L, Artal Sanz M, Coates PJ, Berden JA, Back JW, Muijsers AO, van der Spek H, Grivell LA. Prohibitins act as a membrane-bound chaperone for the stabilization of mitochondrial proteins. Embo J. 2000;19(11):2444–2451. doi: 10.1093/emboj/19.11.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Okamoto K, Kondo-Okamoto N, Ohsumi Y. A landmark protein essential for mitophagy: Atg32 recruits the autophagic machinery to mitochondria. Autophagy. 2009a;5(8):1203–1205. doi: 10.4161/auto.5.8.9830. [DOI] [PubMed] [Google Scholar]
  78. Okamoto K, Kondo-Okamoto N, Ohsumi Y. Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Developmental cell. 2009b;17(1):87–97. doi: 10.1016/j.devcel.2009.06.013. [DOI] [PubMed] [Google Scholar]
  79. Pan Y, Schroeder EA, Ocampo A, Barrientos A, Shadel GS. Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling. Cell Metab. 2011;13(6):668–678. doi: 10.1016/j.cmet.2011.03.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birket MJ, Harold G, Schaeuble K, Birch-Machin MA, Kirkwood TB, von Zglinicki T. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomeredependent senescence. PLoS Biol. 2007;5(5):e110. doi: 10.1371/journal.pbio.0050110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Piper PW. Maximising the yeast chronological lifespan. Sub-cellular biochemistry. 2012;57:145–159. doi: 10.1007/978-94-007-2561-4_7. [DOI] [PubMed] [Google Scholar]
  82. Piper PW, Jones GW, Bringloe D, Harris N, MacLean M, Mollapour M. The shortened replicative life span of prohibitin mutants of yeast appears to be due to defective mitochondrial segregation in old mother cells. Aging Cell. 2002;1(2):149–157. doi: 10.1046/j.1474-9728.2002.00018.x. [DOI] [PubMed] [Google Scholar]
  83. Roberg KJ, Bickel S, Rowley N, Kaiser CA. Control of amino acid permease sorting in the late secretory pathway of Saccharomyces cerevisiae by SEC13, LST4, LST7 and LST8. Genetics. 1997;147(4):1569–1584. doi: 10.1093/genetics/147.4.1569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Ruiz-Roig C, Noriega N, Duch A, Posas F, de Nadal E. The Hog1 SAPK controls the Rtg1/Rtg3 transcriptional complex activity by multiple regulatory mechanisms. Mol Biol Cell. 2012;23(21):4286–4296. doi: 10.1091/mbc.E12-04-0289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Schorling S, Vallee B, Barz WP, Riezman H, Oesterhelt D. Lag1p and Lac1p are essential for the Acyl-CoA-dependent ceramide synthase reaction in Saccharomyces cerevisae. Mol Biol Cell. 2001;12(11):3417–3427. doi: 10.1091/mbc.12.11.3417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Seo JG, Lai CY, Miceli MV, Jazwinski SM. A novel role of peroxin PEX6: suppression of aging defects in mitochondria. Aging Cell. 2007;6(3):405–413. doi: 10.1111/j.1474-9726.2007.00291.x. [DOI] [PubMed] [Google Scholar]
  87. Shore DE, Ruvkun G. A cytoprotective perspective on longevity regulation. Trends Cell Biol. 2013;23(9):409–420. doi: 10.1016/j.tcb.2013.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Simon VR, Karmon SL, Pon LA. Mitochondrial inheritance: cell cycle and actin cable dependence of polarized mitochondrial movements in Saccharomyces cerevisiae. Cell motility and the cytoskeleton. 1997;37(3):199–210. doi: 10.1002/(SICI)1097-0169(1997)37:3<199::AID-CM2>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  89. Sinclair DA, Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast. Cell. 1997;91(7):1033–1042. doi: 10.1016/s0092-8674(00)80493-6. [DOI] [PubMed] [Google Scholar]
  90. Srinivasan V, Kriete A, Sacan A, Jazwinski SM. Comparing the yeast retrograde response and NF-kappa B stress responses: implications for aging. Aging Cell. 2010;9(6):933–941. doi: 10.1111/j.1474-9726.2010.00622.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Stephan JS, Yeh YY, Ramachandran V, Deminoff SJ, Herman PK. The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy. Proc Natl Acad Sci U S A. 2009;106(40):17049–1754. doi: 10.1073/pnas.0903316106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Sun J, Kale SP, Childress AM, Pinswasdi C, Jazwinski SM. Divergent roles of RAS1 and RAS2 in yeast longevity. J Biol Chem. 1994;269(28):18638–18645. [PubMed] [Google Scholar]
  93. Swinnen E, Wilms T, Idkowiak-Baldys J, Smets B, De Snijder P, Accardo S, Ghillebert R, Thevissen K, Cammue B, De Vos D, Bielawski J, Hannun YA, Winderickx J. The protein kinase Sch9 is a key regulator of sphingolipid metabolism in Saccharomyces cerevisiae. Mol Biol Cell. 2014;25(1):196–211. doi: 10.1091/mbc.E13-06-0340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Tanigawa M, Kihara A, Terashima M, Takahara T, Maeda T. Sphingolipids regulate the yeast high-osmolarity glycerol response pathway. Mol Cell Biol. 2012;32(14):2861–2870. doi: 10.1128/MCB.06111-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Tedesco P, Jiang J, Wang J, Jazwinski SM, Johnson TE. Genetic analysis of hyl-1, the C. elegans homolog of LAG1/LASS1. Age. 2008;30(1):43–52. doi: 10.1007/s11357-008-9046-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Teixeira V, Medeiros TC, Vilaca R, Moradas-Ferreira P, Costa V. Reduced TORC1 signaling abolishes mitochondrial dysfunctions and shortened chronological lifespan of Isc1p-deficient cells. Microbial Cell. 2014;1(1):21–36. doi: 10.15698/mic2014.01.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Teufel A, Maass T, Galle PR, Malik N. The longevity assurance homologue of yeast lag1 (Lass) gene family (review) International journal of molecular medicine. 2009;23(2):135–140. [PubMed] [Google Scholar]
  98. Thevissen K, Yen WL, Carmona-Gutierrez D, Idkowiak-Baldys J, Aerts AM, Francois IE, Madeo F, Klionsky DJ, Hannun YA, Cammue BP. Skn1 and Ipt1 negatively regulate autophagy in Saccharomyces cerevisiae. FEMS Microbiol Lett. 2010;303(2):163–168. doi: 10.1111/j.1574-6968.2009.01869.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Traven A, Wong JM, Xu D, Sopta M, Ingles CJ. Interorganellar communication. Altered nuclear gene expression profiles in a yeast mitochondrial dna mutant. J Biol Chem. 2001;276(6):4020–4027. doi: 10.1074/jbc.M006807200. [DOI] [PubMed] [Google Scholar]
  100. Tripathi K, Matmati N, Zheng WJ, Hannun YA, Mohanty BK. Cellular morphogenesis under stress is influenced by the sphingolipid pathway gene ISC1 and DNA integrity checkpoint genes in Saccharomyces cerevisiae. Genetics. 2011;189(2):533–547. doi: 10.1534/genetics.111.132092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O, Wanke V, Anrather D, Ammerer G, Riezman H, Broach JR, De Virgilio C, Hall MN, Loewith R. Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell. 2007;26(5):663–674. doi: 10.1016/j.molcel.2007.04.020. [DOI] [PubMed] [Google Scholar]
  102. Vaena de Avalos S, Okamoto Y, Hannun YA. Activation and localization of inositol phosphosphingolipid phospholipase C, Isc1p, to the mitochondria during growth of Saccharomyces cerevisiae. J Biol Chem. 2004;279(12):11537–11545. doi: 10.1074/jbc.M309586200. [DOI] [PubMed] [Google Scholar]
  103. Vaena de Avalos S, Su X, Zhang M, Okamoto Y, Dowhan W, Hannun YA. The phosphatidylglycerol/cardiolipin biosynthetic pathway is required for the activation of inositol phosphosphingolipid phospholipase C, Isc1p, during growth of Saccharomyces cerevisiae. J Biol Chem. 2005;280(8):7170–7177. doi: 10.1074/jbc.M411058200. [DOI] [PubMed] [Google Scholar]
  104. Venkataraman K, Riebeling C, Bodennec J, Riezman H, Allegood JC, Sullards MC, Merrill AH, Jr, Futerman AH. Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1- independent manner in mammalian cells. J Biol Chem. 2002;277(38):35642–35649. doi: 10.1074/jbc.M205211200. [DOI] [PubMed] [Google Scholar]
  105. Walter L, Baruah A, Chang HW, Pace HM, Lee SS. The homeobox protein CEH- 23 mediates prolonged longevity in response to impaired mitochondrial electron transport chain in C. elegans. PLoS Biol. 2011;9(6):e1001084. doi: 10.1371/journal.pbio.1001084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Wang X, Zuo X, Kucejova B, Chen XJ. Reduced cytosolic protein synthesis suppresses mitochondrial degeneration. Nat Cell Biol. 2008;10(9):1090–1097. doi: 10.1038/ncb1769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Weinberger M, Sampaio-Marques B, Ludovico P, Burhans WC. DNA replication stress-induced loss of reproductive capacity in S. cerevisiae and its inhibition by caloric restriction. Cell Cycle. 2013;12(8):1189–1200. doi: 10.4161/cc.24232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Yang W, Hekimi S. Two modes of mitochondrial dysfunction lead independently to lifespan extension in Caenorhabditis elegans. Aging Cell. 2010;9(3):433–447. doi: 10.1111/j.1474-9726.2010.00571.x. [DOI] [PubMed] [Google Scholar]
  109. Yee C, Yang W, Hekimi S. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell. 2014;157(4):897–909. doi: 10.1016/j.cell.2014.02.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Yorimitsu T, He C, Wang K, Klionsky DJ. Tap42-associated protein phosphatase type 2A negatively regulates induction of autophagy. Autophagy. 2009;5(5):616–624. doi: 10.4161/auto.5.5.8091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Zhang A, Shen Y, Gao W, Dong J. Role of Sch9 in regulating Ras-cAMP signal pathway in Saccharomyces cerevisiae. FEBS Lett. 2011;585(19):3026–3032. doi: 10.1016/j.febslet.2011.08.023. [DOI] [PubMed] [Google Scholar]
  112. Zhang F, Pracheil T, Thornton J, Liu Z. Adenosine Triphosphate (ATP) Is a Candidate Signaling Molecule in the Mitochondria-to-Nucleus Retrograde Response Pathway. Genes. 2013;4(1):86–100. doi: 10.3390/genes4010086. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES