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Complex-I-ty in aging

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Abstract

The role of mitochondrial complex I in aging has been studied in both C. elegans and Drosophila, where RNAi knock down of specific complex I subunits has been shown to extend lifespan. More recently, studies in Drosophila have shown that an increase in mitochondrial activity, including complex I-like activity, can also slow aging. In this review, we discuss this apparent paradox. Improved maintenance of mitochondrial activity, mitochondrial homeostasis, may be responsible for lifespan extension in both cases. Decreased electron transport chain activity caused by reducing complex I subunit expression prompts an increase in stress response signaling that leads to enhanced mitochondrial homeostasis during aging. Increased complex I activity, as well as mitochondrial biogenesis, is expected to both directly counteract the decline in mitochondrial health that occurs during aging and may also increase cellular NAD+ levels, which have been linked to mitochondrial homeostatic mechanisms through activation of sirtuins. We suggest that manipulations that increase or decrease complex I activity both converge on improved mitochondrial homeostasis during aging, resulting in prolonged lifespan.

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References

  • Anderson RM, Weindruch R (2010) Metabolic reprogramming, caloric restriction and aging. Trends Endocrinol Metab 21:134–141

    Article  CAS  Google Scholar 

  • Bahadorani S, Cho J, Lo T, Contreras H, Lawal HO, Krantz DE, Bradley TJ, Walker DW (2010) Neuronal expression of a single-subunit yeast NADH-ubiquinone oxidoreductase (Ndi1) extends Drosophila lifespan. Aging Cell 9:191–202

    Article  CAS  Google Scholar 

  • Bakker BM, Overkamp KM, van Maris AJ, Kötter P, Luttik MA, van Dijken JP, Pronk JT (2001) Stoichiometry and compartmentation of NADH metabolism in Saccharomyces cerevisiae. FEMS Microbiol Rev 25:15–37

    Article  CAS  Google Scholar 

  • Barja G (1999) Mitochondrial oxygen radical generation and leak: sites of production in states 4 and 3, organ specificity, and relation to aging and longevity. J Bioenerg Biomembr 31:347–366

    Article  CAS  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  Google Scholar 

  • Ben-Zvi A, Miller EA, Morimoto RI (2009) Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc Natl Acad Sci U S A 106:14914–14919

    Article  CAS  Google Scholar 

  • Bohensky J, Shapiro IM, Leshinsky S, Terkhorn SP, Adams CS, Srinivas V (2007) HIF-1 regulation of chondrocyte apoptosis: induction of the autophagic pathway. Autophagy 3:207–214

    Article  CAS  Google Scholar 

  • Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE (2006) Bovine complex I is a complex of 45 different subunits. J Biol Chem 281:32724–32727

    Article  CAS  Google Scholar 

  • Cho J, Hur JH, Walker DW (2011) The role of mitochondria in Drosophila aging. Exp Gerontol 46:331–334

    Article  CAS  Google Scholar 

  • Cho J, Hur JH, Graniel J, Benzer S, Walker DW (2012) Expression of yeast NDI1 rescues a Drosophila complex i assembly defect. PLoS One 7:e50644

    Article  CAS  Google Scholar 

  • Clason T, Ruiz T, Schägger H, Peng G, Zickermann V, Brandt U, Michel H, Radermacher M (2010) The structure of eukaryotic and prokaryotic complex I. J Struct Biol 169:81–88

    Article  CAS  Google Scholar 

  • Copeland JM, Cho J, Lo T Jr, Hur JH, Bahadorani S, Arabyan T, Rabie J, Soh J, Walker DW (2009) Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr Biol 19:1591–1598

    Article  CAS  Google Scholar 

  • David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, Kenyon C (2010) Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol 8:e1000450

    Article  Google Scholar 

  • Diaz F, Kotarsky H, Fellman V, Moraes CT (2011) Mitochondrial disorders caused by mutations in respiratory chain assembly factors. Semin Fetal Neonatal Med 16:197–204

    Article  Google Scholar 

  • Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG, Kamath RS, Ahringer J, Kenyon C (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298:2398–2401

    Article  CAS  Google Scholar 

  • Doonan R, McElwee JJ, Matthijssens F, Walker GA, Houthoofd K, Back P, Matscheski A, Vanfleteren JR, Gems D (2008) Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on lifespan in Caenorhabditis elegans. Genes Dev 3:3236–3241

    Article  Google Scholar 

  • Durieux J, Wolff S, Dillin A (2011) The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144:79–91

    Article  CAS  Google Scholar 

  • Efremov RG, Baradaran R, Sazanov LA (2010) The architecture of respiratory complex I. Nature 465:441–445

    Article  CAS  Google Scholar 

  • Gabaldón T, Rainey D, Huynen MA (2005) Tracing the evolution of a large protein complex in the eukaryotes, NADH:ubiquinone oxidoreductase (complex I). J Mol Biol 348:857–870

    Article  Google Scholar 

  • Gems D, Doonan R (2009) Antioxidant defense and aging in C. elegans: is the oxidative damage theory of aging wrong? Cell Cycle 8:1681–1687

    Article  CAS  Google Scholar 

  • Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155:1624–1638

    Article  CAS  Google Scholar 

  • Guarente L (2008) Mitochondria–a nexus for aging, calorie restriction, and sirtuins? Cell 132:171–176

    Article  CAS  Google Scholar 

  • Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300

    Article  CAS  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  Google Scholar 

  • Hur JH, Bahadorani S, Graniel J, Koehler CL, Ulgherait M, Rera M, Jones DL, Walker DW (2013) Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells. Aging (Albany) 5:662–681

    CAS  Google Scholar 

  • Lapointe J, Hekimi S (2010) When a theory of aging ages badly. Cell Mol Life Sci 67:1–8

    Article  CAS  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  Google Scholar 

  • Lee SJ, Hwang AB, Kenyon C (2010) Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol 20:2131–2136

    Article  CAS  Google Scholar 

  • Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370

    Article  Google Scholar 

  • Mair W, Dillin A (2008) Aging and survival: the genetics of life span extension by dietary restriction. Annu Rev Biochem 77:727–754

    Article  CAS  Google Scholar 

  • Mehta R, Steinkraus KA, Sutphin GL, Ramos FJ, Shamieh LS, Huh A, Davis C, Chandler-Brown D, Kaeberlein M (2009) Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science 324:1196–1198

    Article  CAS  Google Scholar 

  • Mimaki M, Wang X, McKenzie M, Thorburn DR, Ryan MT (2012) Understanding mitochondrial complex I assembly in health and disease. Biochim Biophys Acta 1817:851–862

    Article  CAS  Google Scholar 

  • Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Cantó C, Mottis A, Jo YS, Viswanathan M, Schoonjans K, Guarente L, Auwerx J (2013) The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154:430–441

    Article  CAS  Google Scholar 

  • Munkácsy E, Rea SL (2014) The paradox of mitochondrial dysfunction and extended longevity. Exp Gerontol, in press

  • Owusu-Ansah E, Song W, Perrimon N (2013) Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155:699–712

    Article  CAS  Google Scholar 

  • Papa S, Rasmo DD, Technikova-Dobrova Z, Panelli D, Signorile A, Scacco S, Petruzzella V, Papa F, Palmisano G, Gnoni A, Micelli L, Sardanelli AM (2012) Respiratory chain complex I, a main regulatory target of the cAMP/PKA pathway is defective in different human diseases. FEBS Lett 586:568–577

    Article  CAS  Google Scholar 

  • Pearl R (1928) The rate of living, being an account of some experimental studies on the biology of life duration. Knopf, New York

    Google Scholar 

  • Rana A, Rera M, Walker DW (2013) Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc Natl Acad Sci U S A 110:8638–8643

    Article  CAS  Google Scholar 

  • Rea SL, Ventura N, Johnson TE (2007) Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans. PLoS Biol 5:e259

    Article  Google Scholar 

  • Rera M, Monnier V, Tricoire H (2010) Mitochondrial electron transport chain dysfunction during development does not extend lifespan in Drosophila melanogaster. Mech Ageing Dev 131:156–164

    Article  CAS  Google Scholar 

  • Rera M, Bahadorani S, Cho J, Koehler CL, Ulgherait M, Hur JH, Ansari WS, Lo T Jr, Jones DL, Walker DW (2011) Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab 14:623–634

    Article  CAS  Google Scholar 

  • Rera M, Azizi MJ, Walker DW (2013) Organ-specific mediation of lifespan extension: more than a gut feeling? Ageing Res Rev 12:436–444

    Article  CAS  Google Scholar 

  • Ristow M, Zarse K (2010) How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 2:410–418

    Article  Google Scholar 

  • Ross WD (1952) Works of Aristotle. Clarendon, Oxford

    Google Scholar 

  • Rubner M (1908) Das Problem det Lebensdaur und seiner beziehunger zum Wachstum und Ernarnhung. Munich, Germany: Oldenberg.

  • Sanz A, Soikkeli M, Portero-Otín M, Wilson A, Kemppainen E, McIlroy G, Ellilä S, Kemppainen KK, Tuomela T, Lakanmaa M, Kiviranta E, Stefanatos R, Dufour E, Hutz B, Naudí A, Jové M, Zeb A, Vartiainen S, Matsuno-Yagi A, Yagi T, Rustin P, Pamplona R, Jacobs HT (2010) Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction. Proc Natl Acad Sci U S A 107:9105–9110

    Article  CAS  Google Scholar 

  • Tsang WY, Sayles LC, Grad LI, Pilgrim DB, Lemire BD (2001) Mitochondrial respiratory chain deficiency in Caenorhabditis elegans results in developmental arrest and increased life span. J Biol Chem 276:32240–32246

    Article  CAS  Google Scholar 

  • Wallace DC (2005) A Mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407

    Article  CAS  Google Scholar 

  • Wang L, Karpac J, Jasper H (2014) Promoting longevity by maintaining metabolic and proliferative homeostasis. J Exp Biol 217:109–118

    Article  CAS  Google Scholar 

  • Weismann A (1889) Essays upon heredity and kindred biological problems. Clarendon, Oxford

    Google Scholar 

  • Yagi T, Seo BB, Nakamaru-Ogiso E, Marella M, Barber-Singh J, Yamashita T, Matsuno-Yagi A (2006) Possibility of transkingdom gene therapy for complex I diseases. Biochim Biophys Acta 1757:708–714

    Article  CAS  Google Scholar 

  • Yang W, Hekimi S (2010a) A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol 8:e1000556

    Article  Google Scholar 

  • Yang W, Hekimi S (2010b) Two modes of mitochondrial dysfunction lead independently to lifespan extension in Caenorhabditis elegans. Aging Cell 9:433–447

    Article  CAS  Google Scholar 

  • Yang W, Li J, Hekimi S (2007) A Measurable increase in oxidative damage due to reduction in superoxide detoxification fails to shorten the life span of long-lived mitochondrial mutants of Caenorhabditis elegans. Genetics 177:2063–2074

    Article  CAS  Google Scholar 

  • Yee C, Yang W, Hekimi S (2014) The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell 157:897–909

    Article  CAS  Google Scholar 

  • Yuan Y, Kadiyala CS, Ching TT, Hakimi P, Saha S, Xu H, Yuan C, Mullangi V, Wang L, Fivenson E, Hanson RW, Ewing R, Hsu AL, Miyagi M, Feng Z (2012) Enhanced energy metabolism contributes to the extended life span of calorie-restricted Caenorhabditis elegans. J Biol Chem 287:31414–31426

    Article  CAS  Google Scholar 

  • Yun J, Finkel T (2014) Mitohormesis. Cell Metab 19:757–766

    Article  CAS  Google Scholar 

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Acknowledgments

We apologize to our colleagues whose work we could not cite due to space limitations. DWW is supported by the National Institute on Aging (R01 AG037514, R01 AG040288).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biology, Harvey Mudd College, Claremont, CA, 91711, USA

    Jae H. Hur & Devon A. Stork

  2. Department of Physiological Science, University of California, Los Angeles, Los Angeles, CA, 90095, USA

    David W. Walker

  3. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA

    David W. Walker

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  1. Jae H. Hur
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  2. Devon A. Stork
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Correspondence to Jae H. Hur or David W. Walker.

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Hur, J.H., Stork, D.A. & Walker, D.W. Complex-I-ty in aging. J Bioenerg Biomembr 46, 329–335 (2014). https://doi.org/10.1007/s10863-014-9553-0

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  • DOI: https://doi.org/10.1007/s10863-014-9553-0

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