Complex-I-ty in aging
- 447 Downloads
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.
KeywordsElectron transport chain Sirtuin Mitochondrial homeostasis Hormesis
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.
- 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 3:3236–3241CrossRefGoogle 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 155:1624–1638CrossRefGoogle 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) 5:662–681Google Scholar
- Munkácsy E, Rea SL (2014) The paradox of mitochondrial dysfunction and extended longevity. Exp Gerontol, in pressGoogle 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 586:568–577CrossRefGoogle Scholar
- Pearl R (1928) The rate of living, being an account of some experimental studies on the biology of life duration. Knopf, New YorkGoogle Scholar
- Ross WD (1952) Works of Aristotle. Clarendon, OxfordGoogle Scholar
- Rubner M (1908) Das Problem det Lebensdaur und seiner beziehunger zum Wachstum und Ernarnhung. Munich, Germany: Oldenberg.Google Scholar
- 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 107:9105–9110CrossRefGoogle Scholar
- Weismann A (1889) Essays upon heredity and kindred biological problems. Clarendon, OxfordGoogle 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 287:31414–31426CrossRefGoogle Scholar