Metabolism and the UPR mt
2016; Elsevier BV; Volume: 61; Issue: 5 Linguagem: Inglês
10.1016/j.molcel.2016.02.004
ISSN1097-4164
Autores Tópico(s)Adipose Tissue and Metabolism
ResumoDuring mitochondrial dysfunction or the accumulation of unfolded proteins within mitochondria, cells employ a transcriptional response known as the mitochondrial unfolded protein response (UPRmt) to promote cell survival along with the repair and recovery of defective mitochondria. Considerable progress has been made in understanding how cells monitor mitochondrial function and activate the response, as well as in identifying scenarios where the UPRmt plays a protective role, such as during bacterial infection, hematopoietic stem cell maintenance, or general aging. To date, much of the focus has been on the role of the UPRmt in maintaining or re-establishing protein homeostasis within mitochondria by transcriptionally inducing mitochondrial molecular chaperone and protease genes. In this review, we focus on the metabolic adaptations or rewiring mediated by the UPRmt and how this may contribute to the resolution of mitochondrial unfolded protein stress and cell-type-specific physiology. During mitochondrial dysfunction or the accumulation of unfolded proteins within mitochondria, cells employ a transcriptional response known as the mitochondrial unfolded protein response (UPRmt) to promote cell survival along with the repair and recovery of defective mitochondria. Considerable progress has been made in understanding how cells monitor mitochondrial function and activate the response, as well as in identifying scenarios where the UPRmt plays a protective role, such as during bacterial infection, hematopoietic stem cell maintenance, or general aging. To date, much of the focus has been on the role of the UPRmt in maintaining or re-establishing protein homeostasis within mitochondria by transcriptionally inducing mitochondrial molecular chaperone and protease genes. In this review, we focus on the metabolic adaptations or rewiring mediated by the UPRmt and how this may contribute to the resolution of mitochondrial unfolded protein stress and cell-type-specific physiology. Mitochondria are a dynamic network of double membrane bound organelles responsible for the vast majority of ATP generation in nondividing differentiated cells. In addition to housing the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OxPhos) machinery, mitochondria are also important contributors to amino acid, lipid, and nucleotide metabolism. Because mitochondrial function impacts numerous essential cellular and organismal functions, it is perhaps not surprising that mechanisms or pathways have evolved to monitor mitochondrial function and rapidly respond to mitochondrial stress to recover organelle activity. Such pathways are typically referred to as retrograde responses, as the upstream signal initiates at mitochondria and communicates the status to the cytosol and nucleus to impact gene transcription and protein synthesis in a protective manner (Liu and Butow, 2006Liu Z. Butow R.A. Mitochondrial retrograde signaling.Annu. Rev. Genet. 2006; 40: 159-185Crossref PubMed Scopus (512) Google Scholar). Here, we focus on the mitochondrial unfolded protein response (UPRmt), which is a transcriptional response originally discovered to increase mitochondrial localized molecular chaperones and proteases to promote the recovery of organellar protein homeostasis (proteostasis) (Yoneda et al., 2004Yoneda T. Benedetti C. Urano F. Clark S.G. Harding H.P. Ron D. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.J. Cell Sci. 2004; 117: 4055-4066Crossref PubMed Scopus (415) Google Scholar, Zhao et al., 2002Zhao Q. Wang J. Levichkin I.V. Stasinopoulos S. Ryan M.T. Hoogenraad N.J. A mitochondrial specific stress response in mammalian cells.EMBO J. 2002; 21: 4411-4419Crossref PubMed Scopus (706) Google Scholar). However, the UPRmt also promotes a rewiring of cellular metabolism that includes an increase in glycolysis and amino acid catabolism genes with a simultaneous repression of TCA-cycle- and OxPhos-encoding genes potentially to relieve mitochondrial stress and/or alter cellular metabolism to promote survival (Nargund et al., 2015Nargund A.M. Fiorese C.J. Pellegrino M.W. Deng P. Haynes C.M. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).Mol. Cell. 2015; 58: 123-133Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). Many potential mechanisms exist to evaluate mitochondrial activity or function, including monitoring mitochondrial metabolites or products such as ATP or iron-sulfur clusters (Hardie et al., 2015Hardie D.G. Schaffer B.E. Brunet A. AMPK: an energy-sensing pathway with multiple inputs and outputs.Trends Cell Biol. 2015; (S0962-8924(15)00215-9)https://doi.org/10.1016/j.tcb.2015.10.013Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar). However, a number of recent studies demonstrate that an effective strategy is to monitor mitochondrial protein import efficiency (Harbauer et al., 2014Harbauer A.B. Zahedi R.P. Sickmann A. Pfanner N. Meisinger C. The protein import machinery of mitochondria-a regulatory hub in metabolism, stress, and disease.Cell Metab. 2014; 19: 357-372Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar). Mitochondria are composed of over 1,000 proteins, of which ∼99% are encoded by nuclear genes and translated on cytosolic ribosomes. Thus, in order for mitochondria to function properly, these proteins must be imported into mitochondria, where they are appropriately folded and assembled. Transit across the mitochondrial inner membrane not only requires the Tim23 complex but also an intact TCA cycle and OxPhos system that maintains the membrane potential, as well as mitochondrial chaperones located within the matrix (Chacinska et al., 2009Chacinska A. Koehler C.M. Milenkovic D. Lithgow T. Pfanner N. Importing mitochondrial proteins: machineries and mechanisms.Cell. 2009; 138: 628-644Abstract Full Text Full Text PDF PubMed Scopus (987) Google Scholar, Shariff et al., 2004Shariff K. Ghosal S. Matouschek A. The force exerted by the membrane potential during protein import into the mitochondrial matrix.Biophys. 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However, during mitochondrial stress, reduced import efficiency causes many mitochondrial-targeted proteins to accumulate in the cytosol. Most are recognized and targeted for degradation by the proteasome (Wrobel et al., 2015Wrobel L. Topf U. Bragoszewski P. Wiese S. Sztolsztener M.E. Oeljeklaus S. Varabyova A. Lirski M. Chroscicki P. Mroczek S. et al.Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol.Nature. 2015; 524: 485-488Crossref PubMed Scopus (253) Google Scholar) so as to prevent toxicity of mislocalized protein accumulation (Wang and Chen, 2015Wang X. Chen X.J. A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death.Nature. 2015; 524: 481-484Crossref PubMed Scopus (208) Google Scholar). But because ATFS-1 has an NLS, it traffics to the nucleus to activate the UPRmt (Nargund et al., 2012Nargund A.M. Pellegrino M.W. Fiorese C.J. Baker B.M. Haynes C.M. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.Science. 2012; 337: 587-590Crossref PubMed Scopus (627) Google Scholar) (Figure 1A). Included in the stresses that perturb import and activate the UPRmt are depletion of mtDNA (Martinus et al., 1996Martinus R.D. Garth G.P. Webster T.L. Cartwright P. Naylor D.J. Høj P.B. Hoogenraad N.J. Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome.Eur. J. Biochem. 1996; 240: 98-103Crossref PubMed Scopus (249) Google Scholar, Yoneda et al., 2004Yoneda T. Benedetti C. Urano F. Clark S.G. Harding H.P. Ron D. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.J. Cell Sci. 2004; 117: 4055-4066Crossref PubMed Scopus (415) Google Scholar), accumulation of misfolded proteins within mitochondria (Papa and Germain, 2011Papa L. Germain D. Estrogen receptor mediates a distinct mitochondrial unfolded protein response.J. Cell Sci. 2011; 124: 1396-1402Crossref PubMed Scopus (157) Google Scholar, Zhao et al., 2002Zhao Q. Wang J. Levichkin I.V. Stasinopoulos S. Ryan M.T. Hoogenraad N.J. A mitochondrial specific stress response in mammalian cells.EMBO J. 2002; 21: 4411-4419Crossref PubMed Scopus (706) Google Scholar), mitochondrial ribosome impairment (Houtkooper et al., 2013Houtkooper R.H. Mouchiroud L. Ryu D. Moullan N. Katsyuba E. Knott G. Williams R.W. Auwerx J. Mitonuclear protein imbalance as a conserved longevity mechanism.Nature. 2013; 497: 451-457Crossref PubMed Scopus (682) Google Scholar, Moullan et al., 2015Moullan N. Mouchiroud L. Wang X. Ryu D. Williams E.G. Mottis A. Jovaisaite V. Frochaux M.V. Quiros P.M. Deplancke B. et al.Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research.Cell Rep. 2015; (S2211-1247(15)00180-1)https://doi.org/10.1016/j.celrep.2015.02.034Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar), mitochondrial chaperone and protease inhibition (Yoneda et al., 2004Yoneda T. Benedetti C. Urano F. Clark S.G. Harding H.P. Ron D. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.J. Cell Sci. 2004; 117: 4055-4066Crossref PubMed Scopus (415) Google Scholar), OxPhos perturbation (Liu et al., 2014Liu Y. Samuel B.S. Breen P.C. Ruvkun G. Caenorhabditis elegans pathways that surveil and defend mitochondria.Nature. 2014; 508: 406-410Crossref PubMed Scopus (207) Google Scholar, Nargund et al., 2012Nargund A.M. Pellegrino M.W. Fiorese C.J. Baker B.M. Haynes C.M. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.Science. 2012; 337: 587-590Crossref PubMed Scopus (627) Google Scholar), high glucose consumption (Tauffenberger et al., 2016Tauffenberger A. Vaccaro A. Parker J.A. Fragile lifespan expansion by dietary mitohormesis in C. elegans.Aging (Albany, N.Y.). 2016; 8: 50-61PubMed Google Scholar), and high levels of reactive oxygen species (Runkel et al., 2013Runkel E.D. Liu S. Baumeister R. Schulze E. Surveillance-activated defenses block the ROS-induced mitochondrial unfolded protein response.PLoS Genet. 2013; 9: e1003346Crossref PubMed Scopus (132) Google Scholar, Yoneda et al., 2004Yoneda T. Benedetti C. Urano F. Clark S.G. Harding H.P. Ron D. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.J. Cell Sci. 2004; 117: 4055-4066Crossref PubMed Scopus (415) Google Scholar). Thus, the mitochondrial import capacity of the entire organellar network controls expression of a mitochondrial recovery program. Of note, while many of the conditions outlined above have been reported to deplete membrane potential, none of them cause complete membrane depolarization. To our knowledge, the relationship between the inner membrane potential and UPRmt activation has not been explicitly evaluated. Regardless, it is clear that depletion of the mitochondrial inner membrane potential is not necessary to activate the UPRmt (Jin and Youle, 2013Jin S.M. Youle R.J. The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria.Autophagy. 2013; 9: 1750-1757Crossref PubMed Scopus (271) Google Scholar). A second pathway regulated by mitochondrial protein import efficiency is a form of organelle quality control known as mitophagy (Narendra et al., 2008Narendra D. Tanaka A. Suen D.F. Youle R.J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.J. Cell Biol. 2008; 183: 795-803Crossref PubMed Scopus (2858) Google Scholar). Similar to ATFS-1, the kinase PINK1 has an MTS, which allows it to be efficiently imported into healthy organelles and processed, leading to its degradation in the cytosol (Tanaka et al., 2010Tanaka A. Cleland M.M. Xu S. Narendra D.P. Suen D.F. Karbowski M. Youle R.J. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin.J. Cell Biol. 2010; 191: 1367-1380Crossref PubMed Scopus (1014) Google Scholar). However, when import efficiency is severely impaired, PINK1 integrates into the outer membrane of the defective compartment, where it serves several functions. The most well-characterized function involves the subsequent phosphorylation of ubiquitin (Kane et al., 2014Kane L.A. Lazarou M. Fogel A.I. Li Y. Yamano K. Sarraf S.A. Banerjee S. Youle R.J. 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USA. 2010; 107: 378-383Crossref PubMed Scopus (1236) Google Scholar), which ultimately results in isolation of the defective organelle, or subcompartment, and targeting to the lysosome for degradation (Heo et al., 2015Heo J.M. Ordureau A. Paulo J.A. Rinehart J. Harper J.W. The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy.Mol. Cell. 2015; 60: 7-20Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar, Lazarou et al., 2015Lazarou M. Sliter D.A. Kane L.A. Sarraf S.A. Wang C. Burman J.L. Sideris D.P. Fogel A.I. Youle R.J. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.Nature. 2015; 524: 309-314Crossref PubMed Scopus (1533) Google Scholar, McLelland et al., 2014McLelland G.L. Soubannier V. Chen C.X. McBride H.M. Fon E.A. Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control.EMBO J. 2014; 33: 282-295Crossref PubMed Scopus (492) Google Scholar, Yang and Yang, 2013Yang J.Y. Yang W.Y. Bit-by-bit autophagic removal of parkin-labelled mitochondria.Nat. Commun. 2013; 4: 2428Crossref PubMed Scopus (98) Google Scholar). Thus, the mitochondrial network is selfmonitoring as import deficiency directly initiates the downstream activation of at least two protective responses. By activating a protective transcriptional response and eliminating the most defective mitochondria, the UPRmt and mitophagy pathways function to improve or recover the health of the mitochondrial network. In flies, worms, and mammals, the UPRmt includes the induction of mitochondrial proteostasis machinery such as mitochondrial molecular chaperones and proteases as well as antioxidant genes to limit damage due to increased generation of reactive oxygen species (Nargund et al., 2012Nargund A.M. 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Additionally, the UPRmt includes the induction of multiple metabolic pathways including genes required for glycolysis and amino acid catabolism. Interestingly, the UPRmt also limits the accumulation of transcripts that encode the highly expressed TCA cycle and OxPhos components (Nargund et al., 2015Nargund A.M. Fiorese C.J. Pellegrino M.W. Deng P. Haynes C.M. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).Mol. Cell. 2015; 58: 123-133Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar) (Figure 1B). The OxPhos complexes are large, multisubunit structures located within the mitochondrial inner membrane. With the exception of the succinate dehydrogenase complex (complex II), the other three respiratory chain complexes and the ATP synthase are composed of proteins encoded by both the nuclear and mitochondrial genomes (mtDNA). Hundreds of mtDNA copies exist per cell, with multiple copies per mitochondrion. They encode 13 OxPhos subunits as well as tRNAs and rRNAs required for their synthesis. Therefore, to insure efficient complex assembly and biogenesis, transcription from both genomes must be coordinated to promote stoichiometric expression and prevent the accumulation of OxPhos subunits that fail to integrate or assemble into specific complexes (Jovaisaite and Auwerx, 2015Jovaisaite V. Auwerx J. The mitochondrial unfolded protein response—synchronizing genomes.Curr. Opin. Cell Biol. 2015; 33: 74-81Crossref PubMed Scopus (98) Google Scholar). In addition to trafficking to the nucleus during mitochondrial dysfunction and limiting the expression of nuclear-encoded OxPhos components, a percentage of ATFS-1 also accumulates within mitochondria, where it limits the accumulation of the OxPhos transcripts encoded by mtDNA (Figure 1A). ATFS-1-dependent repression of mtDNA-encoded transcripts appears to be direct as ATFS-1 binds the mtDNA promoter region, which contains the same sequence motif that ATFS-1 binds in the nuclear genome to activate mitochondrial proteostasis gene transcription. Combined, these observations suggest that ATFS-1 and the UPRmt simultaneously limit expression of OxPhos components from both genomes to promote efficient stoichiometric expression and assembly of the OxPhos complexes (Nargund et al., 2015Nargund A.M. Fiorese C.J. Pellegrino M.W. Deng P. Haynes C.M. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).Mol. Cell. 2015; 58: 123-133Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). Thus, in addition to increasing the expression of the machinery required to assemble the OxPhos complexes, the UPRmt limits the influx of nascent OxPhos components so as to not overwhelm the protein folding and complex assembly capacity of the defective organelle. Concomitantly, the deficit in ATP production is maintained by increased glycolysis gene expression (Figure 1C). Supporting the role of matching substrate load and mitochondrial proteostasis capacity, additional pathways are also in place to reduce the burden on the potentially deficient mitochondrial protein-folding environment during stress by reducing cytosolic protein synthesis (Baker et al., 2012Baker B.M. Nargund A.M. Sun T. Haynes C.M. Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.PLoS Genet. 2012; 8: e1002760Crossref PubMed Scopus (222) Google Scholar, Wang and Chen, 2015Wang X. Chen X.J. A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death.Nature. 2015; 524: 481-484Crossref PubMed Scopus (208) Google Scholar). The cellular benefits of what appears to be a metabolic shift similar to that observed in rapidly growing cells (Vander Heiden et al., 2009Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10213) Google Scholar) are potentially numerous during mitochondrial dysfunction. An increase in glycolysis is potentially a means to maintain ATP production in the presence of compromised OxPhos, which would promote cell survival as well as the regeneration of defective mitochondria and the OxPhos complexes. However, the induction of glycolysis and repression of TCA cycle and OxPhos transcripts could also serve to rewire cellular metabolism to effect cellular proliferation, growth, or differentiation. Here, we explore the role of UPRmt-mediated metabolic adaptations in several physiologic scenarios where the UPRmt is known to play a role. In addition to inducing genes that promote mitochondrial recovery, the UPRmt also includes xenobiotic detoxification genes as well as innate immunity genes (Liu et al., 2014Liu Y. Samuel B.S. Breen P.C. Ruvkun G. Caenorhabditis elegans pathways that surveil and defend mitochondria.Nature. 2014; 508: 406-410Crossref PubMed Scopus (207) Google Scholar, Pellegrino et al., 2014Pellegrino M.W. Nargund A.M. Kirienko N.V. Gillis R. Fiorese C.J. Haynes C.M. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection.Nature. 2014; 516: 414-417Crossref PubMed Scopus (207) Google Scholar) (Figure 1B). And perhaps not surprisingly, a number of bacterial-produced OxPhos inhibitors such as antimycin and oligomycin, as well as mitochondrial ribosome inhibitors (Moullan et al., 2015Moullan N. Mouchiroud L. Wang X. Ryu D. Williams E.G. Mottis A. Jovaisaite V. Frochaux M.V. Quiros P.M. Deplancke B. et al.Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research.Cell Rep. 2015; (S2211-1247(15)00180-1)https://doi.org/10.1016/j.celrep.2015.02.034Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar), activate the UPRmt in C. elegans and mammals (Liu et al., 2014Liu Y. Samuel B.S. Breen P.C. Ruvkun G. Caenorhabditis elegans pathways that surveil and defend mitochondria.Nature. 2014; 508: 406-410Crossref PubMed Scopus (207) Google Scholar, Pellegrino et al., 2014Pellegrino M.W. Nargund A.M. Kirienko N.V. Gillis R. Fiorese C.J. Haynes C.M. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection.Nature. 2014; 516: 414-417Crossref PubMed Scopus (207) Google Scholar, Runkel et al., 2013Runkel E.D. Liu S. Baumeister R. Schulze E. Surveillance-activated defenses block the ROS-induced mitochondrial unfolded protein response.PLoS Genet. 2013; 9: e1003346Crossref PubMed Scopus (132) Google Scholar). These observations suggest a means to detect pathogenic, or toxic, bacteria by monitoring mitochondrial function and initiating an innate immune response accordingly. In support of this idea, pathogenic strains of Pseudomonas aeruginosa cause mitochondrial dysfunction and activate the UPRmt. Activation of the UPRmt requires the P. aeruginosa virulence response, which includes the production of cyanide (a respiratory chain inhibitor) and iron chelators (Kirienko et al., 2013Kirienko N.V. Kirienko D.R. Larkins-Ford J. Wählby C. Ruvkun G. Ausubel F.M. Pseudomonas aeruginosa disrupts Caenorhabditis elegans iron homeostasis, causing a hypoxic response and death.Cell Host Microbe. 2013; 13: 406-416Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Worms lacking ATFS-1 are sensitive to P. aeruginosa infection, while worms with a constitutively active UPRmt are resistant to the pathogen and limit the intestinal accumulation of the bacteria. Thus, it appears that cells perceive mitochondrial stress or damage as a potential bacterial infection, which may be an important strategy to detect toxic bacteria in nonsterile environments such as the intestine or skin. Increased intestinal clearance of P. aeruginosa suggests the UPRmt provides antibacterial activity, but the role of the UPRmt-mediated metabolic adaptations is less clear. Perhaps the simplest explanation is that in response to the cytochrome c oxidase (complex IV) inhibitor cyanide, the UPRmt increases glycolysis genes to maintain energy levels and limits OxPhos biogenesis so as not to exacerbate the accumulating mitochondrial damage until the animal clears the infection (Melo and Ruvkun, 2012Melo J.A. Ruvkun G. Inactivation of conserved C. elegans genes engages pathogen- and xenobiotic-associated defenses.Cell. 2012; 149: 452-466Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, Pellegrino et al., 2014Pellegrino M.W. Nargund A.M. Kirienko N.V. Gillis R. Fiorese C.J. Haynes C.M. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection.Nature. 2014; 516: 414-417Crossref PubMed Scopus (207) Google Scholar). A decline in mitochondria function is a hallmark of aging (López-Otín et al., 2013López-Otín C. Blasco M.A. Partridge L. Serrano M. Kroemer G. The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (7849) Google Scholar), and multiple studies suggest that increased UPRmt activation can recover or prolong mitochondrial function in a variety of tissues and promote longevity. Modest OxPhos dysfunction in worms, flies, and mice results in lifespan extension and causes UPRmt activation (Durieux et al., 2011Durieux J. Wolff S. Dillin A. The cell-non-autonomous nature of electron transport chain-mediated longevity.Cell. 2011; 144: 79-91Abstract Full Text Full Text PDF PubMed Scopus (722) Google Scholar, Houtkooper et al., 2013Houtkooper R.H. Mouchiroud L. Ryu D. Moullan N. Katsyuba E. Knott G. Williams R.W. Auwerx J. Mitonuclear protein imbalance as a conserved longevity mechanism.Nature. 2013; 497: 451-457Crossref PubMed Scopus (682) Google Scholar, Lapointe et al., 2009Lapointe J. Stepanyan Z. Bigras E. Hekimi S. Reversal of the mitochondrial phenotype and slow development of oxidative biomarkers of aging in long-lived Mclk1+/- mice.J. Biol. Chem. 2009; 284: 20364-20374Crossref PubMed Scopus (74) Google Scholar, Owusu-Ansah et al., 2013Owusu-Ansah E. Song W. Perrimon N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling.Cell. 2013; 155: 699-712Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar). In worms, it has been demonstrated that ATFS-1 (Schieber and Chandel, 2014Schieber M. Chandel N.S. TOR signaling couples oxygen sensing to lifespan in C. elegans.Cell Rep. 2014; 9: 9-15Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar) and other UPRmt signaling components are required for this form of lifespan extension (Durieux et al., 2011Durieux J. Wolff S. Dillin A. The cell-non-autonomous nature of electron transport chain-mediated longevity.Cell. 2011; 144: 79-91Abstract Full Text Full Text PDF PubMed Scopus (722) Google Scholar, Houtkooper et al., 2013Houtkooper R.H. Mouchiroud L. Ryu D. Moullan N. Katsyuba E. Knott G. Williams R.W. Auwerx J. Mitonuclear protein imbalance as a conserved longevity mechanism.Nature. 2013; 497: 451-457Crossref PubMed Scopus (682) Google Scholar). However, it should be noted that UPRmt activation alone is not sufficient to prolong lifespan (Bennett et al., 2014Bennett C.F. Vander Wende H. Simko M. Klum S. Barfield S. Choi H. Pineda V.V. Kaeberlein M. Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans.Nat. Commun. 2014; 5: 3483Crossref PubMed Scopus (138) Google Scholar, Rauthan et al., 2013Rauthan M. Ranji P. Aguilera Pradenas N. Pitot C. Pilon M. The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway.Proc. Natl. Acad. Sci. USA. 2013; 110: 5981-5986Crossref PubMed Scopus (87) Google Scholar), suggesting multiple pathways are in place to respond to mitochondrial stress in addition to the UPRmt. It is unclear which UPRmt-mediated activities specifically contribute to longevity; however, recent work points toward a role in the recovery of mitochondrial function via mitochondrial biogenesis (Houtkooper et al., 2013Houtkooper R.H. Mouchiroud L. Ryu D. Moullan N. Katsyuba E. Knott G. Williams R.W. Auwerx J. Mitonuclear protein imbalance as a conserved longevity mechanism.Nature. 2013; 497: 451-457Crossref PubMed Scopus (682) Google Scholar, Mouchiroud et al., 2013Mouchiroud L. Houtkooper R.H. Moullan N. Katsyuba E. Ryu D. Cantó C. Mottis A. Jo Y.S. Viswanathan M. Schoonjans K. et al.The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling.Cell. 2013; 154: 430-441Abstract Full Text Full Text PDF PubMed Scopus (788) Google Scholar, Nargund et al., 2015Nargund A.M. Fiorese C.J. Pellegrino M.W. Deng P. Haynes C.M. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt).Mol. Cell. 2015; 58: 123-133Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). In aged cells where mitochondria are potentially damaged, recovery of dysfunctional organelles may require a different, perhaps more tightly regulated, program than mitochondrial biogenesis in an otherwise healthy network. Studies in mice and worms have shown that NAD is reduced in aged tissues such as muscle (Cantó et al., 2015Cantó C. Menzies K.J. Auwerx J. NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus.Cell Metab. 2015; 22: 31-53Abstract Full Text Full Text PDF PubMed Scopus (871) Google Scholar, Pirinen et al., 2014Pirinen E. Cantó C. Jo Y.S. Morato L. Zhang H. Menzies K.J. Williams E.G. Mouchiroud L. Moullan N. Hagberg C. et al.Pharmacological inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.Cell Metab. 2014; 19: 1034-1041Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar), as well as in livers of mice fed a high-fat and high-sugar diet (Gariani et al., 2015Gariani K. Menzies K.J. Ryu D. Wegner C.J. Wang X. Ropelle E.R. Moullan N. Zhang H. Perino A. Lemos V. et al.Eliciting the mitochondrial unfolded protein response via NAD(+) repletion reverses fatty liver disease.Hepatology. 2015; https://doi.org/10.1002/hep.28245Crossref PubMed Scopus (230) Google Scholar). NAD is converted to NADH by the TCA cycle within mitochondria, which acts as an electron donor for the respiratory chain, which maintains the membrane potential across the mitochondrial inner membrane and can be used to generate ATP. Impressively, increasing NAD levels by genetic or pharmacologic means promotes mitochondrial function and prolongs lifespan (Andreux et al., 2013Andreux P.A. Houtkooper R.H. Auwerx J. Pharmacological approaches to restore mitochondrial function.Nat. Rev. Drug Discov. 2013; 12: 465-483Crossref PubMed Scopus (280) Google Scholar, Gariani et al., 2015Gariani K. Menzies K.J. Ryu D. Wegner C.J. Wang X. Ropelle E.R. Moullan N. Zhang H. Perino A. Lemos V. et al.Eliciting the mitochondrial unfolded protein response via NAD(+) repletion reverses fatty liver disease.Hepatology. 2015; https://doi.org/10.1002/hep.28245Crossref PubMed Scopus (230) Google Scholar, Mouchiroud et al., 2013Mouchiroud L. Houtkooper R.H. Moullan N. Katsyuba E. Ryu D. Cantó C. Mottis A. Jo Y.S. Viswanathan M. Schoonjans K. et al.The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling.Cell. 2013; 154: 430-441Abstract Full Text Full Text PDF PubMed Scopus (788) Google Scholar). Increased NAD leads to mitochondrial recovery via sirtuin-mediated activation of the transcriptional coactivator PGC-1α, FOXO, as well as UPRmt activation, which combined yields efficient recovery of mitochondrial activity (Mouchiroud et al., 2013Mouchiroud L. Houtkooper R.H. Moullan N. Katsyuba E. Ryu D. Cantó C. Mottis A. Jo Y.S. Viswanathan M. Schoonjans K. et al.The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling.Cell. 2013; 154: 430-441Abstract Full Text Full Text PDF PubMed Scopus (788) Google Scholar). In this context, we anticipate that UPRmt activation orchestrates a very coordinated mitochondrial recovery program by fine-tuning OxPhos and TCA cycle expression to match the protein folding and complex assembly of the defective organelles while simultaneously increasing the mitochondrial proteostasis capacity. Interestingly, the UPRmt may also play a role in maintaining a high NAD/NADH ratio by limiting TCA activity until mitochondrial activity has been recovered when normal TCA cycle gene transcription resumes. Aging can also be attributed to deterioration of tissue-specific stem cells (López-Otín et al., 2013López-Otín C. Blasco M.A. Partridge L. Serrano M. Kroemer G. The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (7849) Google Scholar). However, unlike somatic cells, quiescent stem cells maintain few mitochondria with relatively low metabolic activity (Kohli and Passegué, 2014Kohli L. Passegué E. Surviving change: the metabolic journey of hematopoietic stem cells.Trends Cell Biol. 2014; 24: 479-487Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Interestingly, a recent study found that hematopoietic stem cells (HSCs) utilize a signaling pathway involving a UPRmt to repress mitochondrial biogenesis and OxPhos to coordinate the metabolism required for stem cell maintenance (Mohrin et al., 2015Mohrin M. Shin J. Liu Y. Brown K. Luo H. Xi Y. Haynes C.M. Chen D. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging.Science. 2015; 347: 1374-1377Crossref PubMed Scopus (333) Google Scholar). Hematopoietic stem cell maintenance requires an interaction between the histone deacetylase SIRT7 and the transcription factor NRF1, which regulates the expression of genes that encode mitochondrial ribosome components (Scarpulla et al., 2012Scarpulla R.C. Vega R.B. Kelly D.P. Transcriptional integration of mitochondrial biogenesis.Trends Endocrinol. Metab. 2012; 23: 459-466Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar). In this context, SIRT7 expression is increased by mitochondrial protein folding stress associated with the burst of mitochondria biogenesis that occurs during stem cell proliferation. By inhibiting NRF1 activity, SIRT7 limits mitochondrial biogenesis and OxPhos, preserving stem cell metabolism (Figure 2). Therefore, SIRT7 promotes the maintenance of a pristine mitochondrial protein-folding environment, keeping the organelles and the stem cells in a “youthful” state. Consistent with this idea, HSCs lacking SIRT7 have increased mitochondrial stress and an increased propensity to proliferate. Thus, HSCs require SIRT7 to limit mitochondrial stress and proliferation (Mohrin et al., 2015Mohrin M. Shin J. Liu Y. Brown K. Luo H. Xi Y. Haynes C.M. Chen D. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging.Science. 2015; 347: 1374-1377Crossref PubMed Scopus (333) Google Scholar), which maintains their regenerative function (Miyamoto et al., 2007Miyamoto K. Araki K.Y. Naka K. Arai F. Takubo K. Yamazaki S. Matsuoka S. Miyamoto T. Ito K. Ohmura M. et al.Foxo3a is essential for maintenance of the hematopoietic stem cell pool.Cell Stem Cell. 2007; 1: 101-112Abstract Full Text Full Text PDF PubMed Scopus (684) Google Scholar). Indeed, SIRT7 expression decreases in aged mice where HSC maintenance fails, leading to a reduction in white blood cell number (Mohrin et al., 2015Mohrin M. Shin J. Liu Y. Brown K. Luo H. Xi Y. Haynes C.M. Chen D. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging.Science. 2015; 347: 1374-1377Crossref PubMed Scopus (333) Google Scholar), suggesting that by simply limiting OxPhos complex biogenesis and unfolded protein accumulation, stem cell function can be preserved during aging. We have highlighted scenarios identified in multiple organisms where the UPRmt has been documented to play a protective role, focusing on the potential protective outputs of UPRmt-mediated metabolic regulation rather than the maintenance of mitochondrial proteostasis. However, it should be noted that while the regulation of the UPRmt in C. elegans relies on the transcription factor ATFS-1, less is known regarding the regulation of the UPRmt in mammals or flies. A pressing question in the field is whether the UPRmt-related observations in flies or mammals are regulated via mitochondrial protein import efficiency or through an alternative means. Unfortunately, homology searches do not yield candidates with especially significant homology beyond the DNA binding domain. Interestingly, the yeast transcription factor Hap1 was recently found to harbor both an MTS and an NLS (Williams et al., 2014Williams C.C. Jan C.H. Weissman J.S. Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling.Science. 2014; 346: 748-751Crossref PubMed Scopus (225) Google Scholar), suggesting it is regulated similarly to ATFS-1. Consistent with Hap1 responding to mitochondrial protein import impairment, it is activated when oxygen and heme are limiting and activates genes that promote heme biogenesis (Kwast et al., 1998Kwast K.E. Burke P.V. Poyton R.O. Oxygen sensing and the transcriptional regulation of oxygen-responsive genes in yeast.J. Exp. Biol. 1998; 201: 1177-1195Crossref PubMed Google Scholar). Because multiple mammalian transcription factors have putative MTSs (Claros and Vincens, 1996Claros M.G. Vincens P. Computational method to predict mitochondrially imported proteins and their targeting sequences.Eur. J. Biochem. 1996; 241: 779-786Crossref PubMed Scopus (1375) Google Scholar) and have been found to localize to mitochondria (Marinov et al., 2014Marinov G.K. Wang Y.E. Chan D. Wold B.J. Evidence for site-specific occupancy of the mitochondrial genome by nuclear transcription factors.PLoS ONE. 2014; 9: e84713Crossref PubMed Scopus (22) Google Scholar), we are optimistic a similar mode of regulation will be uncovered. However, other means of sensing and responding to mitochondrial stress should not be excluded.
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