A fundamental impact of mitochondria on biological aging has been suggested decades ago. One prominent theory explains aging as the result of the age-related accumulation of random molecular damage of biomolecules resulting from the reaction of reactive oxygen species, the majority of which are generated in mitochondria. Although this concept appeared to be very attractive and strongly influenced aging research, in recent years more and more data accumulated which seem to contradict this theory. However, since these data are derived from reductionist approaches and do not integrate the various components and pathways which are affected as a result of a primary experimental intervention, they are prone to misinterpretation and have to be taken with some caution. Here, after a general introduction of mitochondrial function, we discuss the relevance of various pathways which are involved in keeping mitochondria functional over time. Moreover, we provide examples which emphasize the importance of a critical interpretation of experimental data and the necessity for a holistic analysis of the aging process. The success of such a systems biology approach is strongly dependent on the development of methods for data mining and an efficient analysis and modeling of the huge data sets that are raised.

Keywords:
Mitochondria, Aging, Reactive oxygen species, Protein quality control, Mitophagy, Apoptosis, Mitochondrial dynamics
1.
Fischer F, Hamann A, Osiewacz HD: Mitochondrial quality control: an integrated network of pathways. Trends Biochem Sci 2012;37:284-292.
2.
Weber TA, Reichert AS: Impaired quality control of mitochondria: aging from a new perspective. Exp Gerontol 2010;45:503-511.
3.
Osiewacz HD: Genes, mitochondria and aging in filamentous fungi. Ageing Res Rev 2002;28:1-18.
4.
Osiewacz HD: Genetic regulation of aging. J Mol Med 1997;75:715-727.
5.
Osiewacz HD, Hermanns J: The role of mitochondrial DNA rearrangements in aging and human diseases. Aging (Milano) 1992;4:273-286.
6.
Wallace DC: Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 2010;51:440-450.
7.
Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly Y, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG: Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 2004;429:417-423.
8.
Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA: Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 2005;309:481-484.
9.
Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS, Prolla TA, Loeb LA: Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 2007;39:540-543.
10.
Harman D: The biologic clock: the mitochondria? J Am Geriatr Soc 1972;20:145-147.
11.
Lapointe J, Hekimi S: When a theory of aging ages badly. Cell Mol Life Sci 2010;67:1-8.
12.
Luce K, Osiewacz HD: Increasing organismal healthspan by enhancing mitochondrial protein quality control. Nat Cell Biol 2009;11:852-858.
13.
Zintel S, Schwitalla D, Luce K, Hamann A, Osiewacz HD: Increasing mitochondrial superoxide dismutase abundance leads to impairments in protein quality control and ROS scavenging systems and to lifespan shortening. Exp Gerontol 2010;45:525-532.
14.
Doonan R, McElwee JJ, Matthijssens F, Walker GA, Houthoofd K, Back P, Matscheski A, Vanfleteren JR, Gems D: Against the oxidative damage theory of aging: Superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 2008;22:3236-3241.
15.
Kowald A, Hamann A, Zintel S, Ullrich S, Klipp E, Osiewacz HD: A systems biological analysis links ROS metabolism to mitochondrial protein quality control. Mech Ageing Dev 2012;133:331-337.
16.
Cantu D, Schaack J, Patel M: Oxidative inactivation of mitochondrial aconitase results in iron and H2O2-mediated neurotoxicity in rat primary mesencephalic cultures. PLoS One 2009;4:e7095.
17.
Gardner PR, Raineri I, Epstein LB, White CW: Superoxide radical and iron modulate aconitase activity in mammalian cells. J Biol Chem 1995;270:13399-13405.
18.
Tatsuta T, Langer T: Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J 2008;27:306-314.
19.
Friguet B, Bulteau AL, Petropoulos I: Mitochondrial protein quality control: implications in ageing. Biotechnol J 2008;3:757-764.
20.
Adam C, Picard M, Déquard-Chablat M, Sellem CH, Denmat SH, Contamine V: Biological roles of the Podospora anserina mitochondrial Lon protease and the importance of its N-domain. PLoS One 2012;7:e38138.
21.
Weil A, Luce K, Dröse S, Wittig I, Brandt U, Osiewacz HD: Unmasking a temperature-dependent effect of the P. anserina i-AAA protease on aging and development. Cell Cycle 2011;10:4280-4290.
22.
Fischer F, Weil A, Hamann A, Osiewacz HD: Human CLPP reverts the longevity phenotype of a fungal ClpP deletion strain. Nat Commun 2013;4:1397.
23.
Taylor EB, Rutter J: Mitochondrial quality control by the ubiquitin-proteasome system. Biochem Soc Trans 2011;39:1509-1513.
24.
Jeon HB, Choi ES, Yoon JH, Hwang JH, Chang JW, Lee EK, Choi HW, Park ZY, Yoo YJ: A proteomics approach to identify the ubiquitinated proteins in mouse heart. Biochem Biophys Res Commun 2007;357:731-736.
25.
Scheckhuber CQ, Erjavec N, Tinazli A, Hamann A, Nyström T, Osiewacz HD: Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models. Nat Cell Biol 2007;9:99-105.
26.
Yang CC, Chen D, Lee SS, Walter L: The dynamin-related protein DRP-1 and the insulin signaling pathway cooperate to modulate C. elegans longevity. Aging Cell 2011;10:724-728.
27.
Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO, Masuda K, Otera H, Nakanishi Y, Nonaka I, Goto Y, Taguchi N, Morinaga H, Maeda M, Takayanagi R, Yokota S, Mihara K: Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 2009;11:958-966.
28.
Youle RJ, van der Bliek AM: Mitochondrial fission, fusion, and stress. Science 2012;337:1062-1065.
29.
Kelly GL, Strasser A: The essential role of evasion from cell death in cancer. Adv Cancer Res 2011;111:39-96.
30.
Hamann A, Brust D, Osiewacz HD: Apoptosis pathways in fungal growth, development and ageing. Trends Microbiol 2008;16:276-283.
31.
Brust D, Daum B, Breunig C, Hamann A, Kühlbrandt W, Osiewacz HD: Cyclophilin D links programmed cell death and organismal aging in Podospora anserina. Aging Cell 2010;9:761-775.
32.
Groebe K, Krause F, Kunstmann B, Unterluggauer H, Reifschneider NH, Scheckhuber CQ, Sastri C, Stegmann W, Wozny W, Schwall GP, Poznanovic S, Dencher NA, Jansen-Dürr P, Osiewacz HD, Schrattenholz A: Differential proteomic profiling of mitochondria from Podospora anserina, rat and human reveals distinct patterns of age-related oxidative changes. Exp Gerontol 2007;42:887-898.
33.
Marzetti E, Hwang JCY, Lees HA, Wohlgemuth SE, Dupont-Versteegden EE, Carter CS, Bernabei R, Leeuwenburgh C: Mitochondrial death effectors: relevance to sarcopenia and disuse muscle atrophy. Biochim Biophys Acta 2009;1800:235-244.
34.
Hiona A, Sanz A, Kujoth GC, Pamplona R, Seo AY, Hofer T, Someya S, Miyakawa T, Nakayama C, Samhan-Arias AK, Servais S, Barger JL, Portero-Otín M, Tanokura M, Prolla TA, Leeuwenburgh C: Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PLoS One 2010;5:e11468.
35.
Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A, Sinclair DA: Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany, N.Y.) 2010;2:914-923.
36.
Hoppins S, Nunnari J: Mitochondrial dynamics and apoptosis-the ER connection. Science 2012;337:1052-1054.
37.
Lu Y, Rolland SG, Conradt B: A molecular switch that governs mitochondrial fusion and fission mediated by the BCL2-like protein CED-9 of Caenorhabditis elegans. Proc Natl Acad Sci USA 2011;108:E813-E822.
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2013
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