Skip to main content

Advertisement

Log in

Mitochondrial translation and cellular stress response

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Mitochondria are organelles critical for the functionality of eukaryotic cells. One of their most prominent functions is energy conversion, thereby producing most of the cellular ATP. Energy conversion relies on the oxidative phosphorylation system, an ensemble of large protein complexes that include the respiratory chain and the ATP synthase. Biogenesis of this machinery requires the coordination of two separate genetic systems, namely nuclear and mitochondrial gene expression. Recent research into the molecular causes of aging have revealed a prominent contribution of mitochondrial gene expression on many aspects of degenerative processes that typically involve cellular stress signaling pathways. In this review, we summarize recent developments in attempting to identify the molecular mechanism by which dysfunction of mitochondrial gene expression activates cellular stress signaling pathways and how this affects organismal aging. By comparing data obtained in various model organisms, we identify conserved and species-specific aspects of this mitochondria-to-nucleus signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aldridge JE, Horibe T, Hoogenraad NJ (2007) Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements. PLoS ONE 2:e874

    Article  PubMed  PubMed Central  Google Scholar 

  • Archibald JM (2015) Endosymbiosis and eukaryotic cell evolution. Curr Biol 25:R911–R921

    Article  CAS  PubMed  Google Scholar 

  • Arnold I, Wagner-Ecker M, Ansorge W, Langer T (2006) Evidence for a novel mitochondria-to-nucleus signalling pathway in respiring cells lacking i-AAA protease and the ABC-transporter Mdl1. Gene 367:74–88

    Article  CAS  PubMed  Google Scholar 

  • Baker BM, Nargund AM, Sun T, Haynes CM (2012) Protective coupling of mitochondrial function and protein synthesis via the eIF2alpha kinase GCN-2. PLoS Genet 8:e1002760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barrientos A, Zambrano A, Tzagoloff A (2004) Mss51p and Cox14p jointly regulate mitochondrial Cox1p expression in Saccharomyces cerevisiae. EMBO J 23:3472–3482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beck T, Hall MN (1999) The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402:689–692

    Article  CAS  PubMed  Google Scholar 

  • Bennett CF, Vander Wende H, Simko M, Klum S, Barfield S, Choi H, Pineda VV, Kaeberlein M (2014) Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans. Nat Commun 5:3483

    Article  PubMed  PubMed Central  Google Scholar 

  • Bhola PD, Letai A (2016) Mitochondria-judges and executioners of cell death sentences. Mol Cell 61:695–704

    Article  CAS  PubMed  Google Scholar 

  • Boczonadi V, Horvath R (2014) Mitochondria: impaired mitochondrial translation in human disease. Int J Biochem Cell Biol 48:77–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bratic A, Larsson NG (2013) The role of mitochondria in aging. J Clin Invest 123:951–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caballero A, Ugidos A, Liu B, Oling D, Kvint K, Hao X, Mignat C, Nachin L, Molin M, Nystrom T (2011) Absence of mitochondrial translation control proteins extends life span by activating sirtuin-dependent silencing. Mol Cell 42:390–400

    Article  CAS  PubMed  Google Scholar 

  • Chacinska A, Koehler CM, Milenkovic D, Lithgow T, Pfanner N (2009) Importing mitochondrial proteins: machineries and mechanisms. Cell 138:628–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cherkasova VA, Hinnebusch AG (2003) Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. Genes Dev 17:859–872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couvillion MT, Soto IC, Shipkovenska G, Churchman LS (2016) Synchronized mitochondrial and cytosolic translation programs. Nature 533:499–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delaney JR, Ahmed U, Chou A, Sim S, Carr D, Murakami CJ, Schleit J, Sutphin GL, An EH, Castanza A, Fletcher M, Higgins S, Jelic M, Klum S, Muller B, Peng ZJ, Rai D, Ros V, Singh M, Wende HV, Kennedy BK, Kaeberlein M (2013) Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging. Aging Cell 12:156–166

    Article  CAS  PubMed  Google Scholar 

  • Dilova I, Chen CY, Powers T (2002) Mks1 in concert with TOR signaling negatively regulates RTG target gene expression in S. cerevisiae. Curr Biol 12:389–395

    Article  CAS  PubMed  Google Scholar 

  • Dilova I, Aronova S, Chen JC, Powers T (2004) Tor signaling and nutrient-based signals converge on Mks1p phosphorylation to regulate expression of Rtg1.Rtg3p-dependent target genes. J Biol Chem 279:46527–46535

    Article  CAS  PubMed  Google Scholar 

  • Dong J, Qiu H, Garcia-Barrio M, Anderson J, Hinnebusch AG (2000) Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol Cell 6:269–279

    Article  CAS  PubMed  Google Scholar 

  • Friedman JR, Nunnari J (2014) Mitochondrial form and function. Nature 505:335–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galdieri L, Mehrotra S, Yu S, Vancura A (2010) Transcriptional regulation in yeast during diauxic shift and stationary phase. OMICS 14:629–638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorner W, Durchschlag E, Martinez-Pastor MT, Estruch F, Ammerer G, Hamilton B, Ruis H, Schuller C (1998) Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity. Genes Dev 12:586–597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gruschke S, Römpler K, Hildenbeutel M, Kehrein K, Kühl I, Bonnefoy N, Ott M (2012) The Cbp3-Cbp6 complex coordinates cytochrome b synthesis with bc 1 complex assembly in yeast mitochondria. J Cell Biol 199:137–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147

    Article  CAS  PubMed  Google Scholar 

  • Harmel J, Ruzzenente B, Terzioglu M, Spahr H, Falkenberg M, Larsson NG (2013) The leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) does not activate transcription in mammalian mitochondria. J Biol Chem 288:15510–15519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haynes CM, Petrova K, Benedetti C, Yang Y, Ron D (2007) ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. Dev Cell 13:467–480

    Article  CAS  PubMed  Google Scholar 

  • Haynes CM, Yang Y, Blais SP, Neubert TA, Ron D (2010) The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans. Mol Cell 37:529–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heeren G, Rinnerthaler M, Laun P, von Seyerl P, Kossler S, Klinger H, Hager M, Bogengruber E, Jarolim S, Simon-Nobbe B, Schuller C, Carmona-Gutierrez D, Breitenbach-Koller L, Muck C, Jansen-Durr P, Criollo A, Kroemer G, Madeo F, Breitenbach M (2009) The mitochondrial ribosomal protein of the large subunit, Afo1p, determines cellular longevity through mitochondrial back-signaling via TOR1. Aging (Albany NY) 1:622–636

    Article  CAS  Google Scholar 

  • Horibe T, Hoogenraad NJ (2007) The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response. PLoS ONE 2:e835

    Article  PubMed  PubMed Central  Google Scholar 

  • Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G, Williams RW, Auwerx J (2013) Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497:451–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jia Y, Rothermel B, Thornton J, Butow RA (1997) A basic helix-loop-helix-leucine zipper transcription complex in yeast functions in a signaling pathway from mitochondria to the nucleus. Mol Cell Biol 17:1110–1117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaida D, Yashiroda H, Toh-e A, Kikuchi Y (2002) Yeast Whi2 and Psr1-phosphatase form a complex and regulate STRE-mediated gene expression. Genes Cells 7:543–552

    Article  CAS  PubMed  Google Scholar 

  • Kraakman L, Lemaire K, Ma P, Teunissen AW, Donaton MC, Van Dijck P, Winderickx J, de Winde JH, Thevelein JM (1999) A Saccharomyces cerevisiae G-protein coupled receptor, Gpr1, is specifically required for glucose activation of the cAMP pathway during the transition to growth on glucose. Mol Microbiol 32:1002–1012

    Article  CAS  PubMed  Google Scholar 

  • Lagouge M, Larsson NG (2013) The role of mitochondrial DNA mutations and free radicals in disease and ageing. J Intern Med 273:529–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G (2003) A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 33:40–48

    Article  CAS  PubMed  Google Scholar 

  • Lemieux J, Lakowski B, Webb A, Meng Y, Ubach A, Bussiere F, Barnes T, Hekimi S (2001) Regulation of physiological rates in Caenorhabditis elegans by a tRNA-modifying enzyme in the mitochondria. Genetics 159:147–157

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liao XS, Small WC, Srere PA, Butow RA (1991) Intramitochondrial functions regulate nonmitochondrial citrate synthase (CIT2) expression in Saccharomyces cerevisiae. Mol Cell Biol 11:38–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Z, Butow RA (2006) Mitochondrial retrograde signaling. Annu Rev Genet 40:159–185

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Sekito T, Spirek M, Thornton J, Butow RA (2003) Retrograde signaling is regulated by the dynamic interaction between Rtg2p and Mks1p. Mol Cell 12:401–411

    Article  CAS  PubMed  Google Scholar 

  • Long X, Muller F, Avruch J (2004) TOR action in mammalian cells and in Caenorhabditis elegans. Curr Top Microbiol Immunol 279:115–138

    CAS  PubMed  Google Scholar 

  • Longo VD, Shadel GS, Kaeberlein M, Kennedy B (2012) Replicative and chronological aging in Saccharomyces cerevisiae. Cell Metab 16:18–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinus RD, Garth GP, Webster TL, Cartwright P, Naylor DJ, Hoj PB, Hoogenraad NJ (1996) Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur J Biochem 240:98–103

    Article  CAS  PubMed  Google Scholar 

  • Miceli MV, Jiang JC, Tiwari A, Rodriguez-Quinones JF, Jazwinski SM (2011) Loss of mitochondrial membrane potential triggers the retrograde response extending yeast replicative lifespan. Front Genet 2:102

    PubMed  Google Scholar 

  • Moullan N, Mouchiroud L, Wang X, Ryu D, Williams EG, Mottis A, Jovaisaite V, Frochaux MV, Quiros PM, Deplancke B, Houtkooper RH, Auwerx J (2015) Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Rep (in press)

  • Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM (2012) Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337:587–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nargund AM, Fiorese CJ, Pellegrino MW, Deng P, Haynes CM (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol Cell 58:123–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neupert W (2015) A perspective on transport of proteins into mitochondria: a myriad of open questions. J Mol Biol 427:1135–1158

    Article  CAS  PubMed  Google Scholar 

  • Nolden M, Ehses S, Koppen M, Bernacchia A, Rugarli EI, Langer T (2005) The m-AAA protease defective in hereditary spastic paraplegia controls ribosome assembly in mitochondria. Cell 123:277–289

    Article  CAS  PubMed  Google Scholar 

  • Ocampo A, Barrientos A (2011) Quick and reliable assessment of chronological life span in yeast cell populations by flow cytometry. Mech Ageing Dev 132:315–323

    Article  CAS  PubMed  Google Scholar 

  • Ocampo A, Liu J, Schroeder EA, Shadel GS, Barrientos A (2012) Mitochondrial respiratory thresholds regulate yeast chronological life span and its extension by caloric restriction. Cell Metab 16:55–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ott M, Amunts A, Brown A (2016) Organization and regulation of mitochondrial protein synthesis. Annu Rev Biochem (in press)

  • Papa L, Germain D (2011) Estrogen receptor mediates a distinct mitochondrial unfolded protein response. J Cell Sci 124:1396–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rak M, Tzagoloff A (2009) F1-dependent translation of mitochondrially encoded Atp6p and Atp8p subunits of yeast ATP synthase. Proc Natl Acad Sci U S A 106:18509–18514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rath E, Berger E, Messlik A, Nunes T, Liu B, Kim SC, Hoogenraad N, Sans M, Sartor RB, Haller D (2012) Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation. Gut 61:1269–1278

    Article  CAS  PubMed  Google Scholar 

  • Richter U, Lahtinen T, Marttinen P, Myohanen M, Greco D, Cannino G, Jacobs HT, Lietzen N, Nyman TA, Battersby BJ (2013) A mitochondrial ribosomal and RNA decay pathway blocks cell proliferation. Curr Biol 23:535–541

    Article  CAS  PubMed  Google Scholar 

  • Richter U, Lahtinen T, Marttinen P, Suomi F, Battersby BJ (2015) Quality control of mitochondrial protein synthesis is required for membrane integrity and cell fitness. J Cell Biol 211:373–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rolland F, De Winde JH, Lemaire K, Boles E, Thevelein JM, Winderickx J (2000) Glucose-induced cAMP signalling in yeast requires both a G-protein coupled receptor system for extracellular glucose detection and a separable hexose kinase-dependent sensing process. Mol Microbiol 38:348–358

    Article  CAS  PubMed  Google Scholar 

  • Rothermel BA, Thornton JL, Butow RA (1997) Rtg3p, a basic helix-loop-helix/leucine zipper protein that functions in mitochondrial-induced changes in gene expression, contains independent activation domains. J Biol Chem 272:19801–19807

    Article  CAS  PubMed  Google Scholar 

  • Sagan L (1967) On the origin of mitosing cells. J Theor Biol 14:255–274

    Article  CAS  PubMed  Google Scholar 

  • Sekito T, Thornton J, Butow RA (2000) Mitochondria-to-nuclear signaling is regulated by the subcellular localization of the transcription factors Rtg1p and Rtg3p. Mol Biol Cell 11:2103–2115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sekito T, Liu Z, Thornton J, Butow RA (2002) RTG-dependent mitochondria-to-nucleus signaling is regulated by MKS1 and is linked to formation of yeast prion [URE3]. Mol Biol Cell 13:795–804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shutt TE, Shadel GS (2010) A compendium of human mitochondrial gene expression machinery with links to disease. Environ Mol Mutagen 51:360–379

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles--a cause of aging in yeast. Cell 91:1033–1042

    Article  CAS  PubMed  Google Scholar 

  • Sun N, Youle RJ, Finkel T (2016) The mitochondrial basis of aging. Mol Cell 61:654–666

    Article  CAS  PubMed  Google Scholar 

  • Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT, Larsson NG (2005) Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci U S A 102:17993–17998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 (2007) Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell 26:663–674

    Article  CAS  PubMed  Google Scholar 

  • Vlanti A, Rousakis A, Syntichaki P (2013) GCN2 and TOR converge on aging. Aging (Albany NY) 5:584–585

    Article  CAS  Google Scholar 

  • Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Chen XJ (2015) A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death. Nature 524:481–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wasko BM, Kaeberlein M (2014) Yeast replicative aging: a paradigm for defining conserved longevity interventions. FEMS Yeast Res 14:148–159

    Article  CAS  PubMed  Google Scholar 

  • Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L, Longo VD (2008) Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet 4:e13

    Article  PubMed  PubMed Central  Google Scholar 

  • Weraarpachai W, Antonicka H, Sasarman F, Seeger J, Schrank B, Kolesar JE, Lochmuller H, Chevrette M, Kaufman BA, Horvath R, Shoubridge EA (2009) Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet 41:833–837

    Article  CAS  PubMed  Google Scholar 

  • Wrobel L, Topf U, Bragoszewski P, Wiese S, Sztolsztener ME, Oeljeklaus S, Varabyova A, Lirski M, Chroscicki P, Mroczek S, Januszewicz E, Dziembowski A, Koblowska M, Warscheid B, Chacinska A (2015) Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524:485–488

    Article  CAS  PubMed  Google Scholar 

  • Yang F, Gao Y, Li Z, Chen L, Xia Z, Xu T, Qin Y (2014) Mitochondrial EF4 links respiratory dysfunction and cytoplasmic translation in Caenorhabditis elegans. Biochim Biophys Acta 1837:1674–1683

    Article  CAS  PubMed  Google Scholar 

  • Yoneda T, Benedetti C, Urano F, Clark SG, Harding HP, Ron D (2004) Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J Cell Sci 117:4055–4066

    Article  CAS  PubMed  Google Scholar 

  • Zhang F, Pracheil T, Thornton J, Liu Z (2013) Adenosine Triphosphate (ATP) Is a candidate signaling molecule in the mitochondria-to-nucleus retrograde response pathway. Genes (Basel) 4:86–100

    Google Scholar 

  • Zhao Q, Wang J, Levichkin IV, Stasinopoulos S, Ryan MT, Hoogenraad NJ (2002) A mitochondrial specific stress response in mammalian cells. EMBO J 21:4411–4419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We wish to thank Hannah Dawitz for critically reading the manuscript. Work in the laboratory was supported by grants from the Swedish research council, the Carl-Tryggers foundation, the Knut and Alice Wallenberg foundation and the Swedish foundation for strategic research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin Ott.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suhm, T., Ott, M. Mitochondrial translation and cellular stress response. Cell Tissue Res 367, 21–31 (2017). https://doi.org/10.1007/s00441-016-2460-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-016-2460-4

Keywords

Navigation