Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production
Aleksandra Trifunovic,Anna Hansson,Anna Wredenberg,Anja T. Rovio,Eric Dufour,Ivan Khvorostov,Johannes N. Spelbrink,Rolf Wibom,Howard T. Jacobs,Nils-Göran Larsson +9 more
TLDR
The premature aging phenotypes in mt DNA mutator mice are thus not generated by a vicious cycle of massively increased oxidative stress accompanied by exponential accumulation of mtDNA mutations, and it is proposed that respiratory chain dysfunction per se is the primary inducer of premature aging in mtDNA mutATOR mice.Abstract:
The mitochondrial theory of aging proposes that reactive oxygen species (ROS) generated inside the cell will lead, with time, to increasing amounts of oxidative damage to various cell components. The main site for ROS production is the respiratory chain inside the mitochondria and accumulation of mtDNA mutations, and impaired respiratory chain function have been associated with degenerative diseases and aging. The theory predicts that impaired respiratory chain function will augment ROS production and thereby increase the rate of mtDNA mutation accumulation, which, in turn, will further compromise respiratory chain function. Previously, we reported that mice expressing an error-prone version of the catalytic subunit of mtDNA polymerase accumulate a substantial burden of somatic mtDNA mutations, associated with premature aging phenotypes and reduced lifespan. Here we show that these mtDNA mutator mice accumulate mtDNA mutations in an approximately linear manner. The amount of ROS produced was normal, and no increased sensitivity to oxidative stress-induced cell death was observed in mouse embryonic fibroblasts from mtDNA mutator mice, despite the presence of a severe respiratory chain dysfunction. Expression levels of antioxidant defense enzymes, protein carbonylation levels, and aconitase enzyme activity measurements indicated no or only minor oxidative stress in tissues from mtDNA mutator mice. The premature aging phenotypes in mtDNA mutator mice are thus not generated by a vicious cycle of massively increased oxidative stress accompanied by exponential accumulation of mtDNA mutations. We propose instead that respiratory chain dysfunction per se is the primary inducer of premature aging in mtDNA mutator mice.read more
Citations
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Mitochondrial DNA mutations in human disease.
TL;DR: This review considers the basic principles of mitochondrial genetics which govern both the behaviour and investigation of pathogenic mtDNA mutations summarizing recent advances, and an assessment of the ongoing debate into the role of somatic mt DNA mutations in neurodegenerative disease, ageing and cancer.
Journal ArticleDOI
The role of mitochondria in aging
Ana Bratic,Nils-Göran Larsson +1 more
TL;DR: The caveats of the traditional mitochondrial free radical theory of aging are discussed and other possible mechanisms, including insulin/IGF-1 signaling and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process are highlighted.
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p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both
TL;DR: It is demonstrated that mitochondria are aggregated by p62, following its recruitment by Parkin in a VDAC1-independent manner, and it is suggested that proteins other than p62 are likely required for mitophagy downstream of Parkin substrates other than VD AC1.
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Mitochondrial dysfunction in atherosclerosis
TL;DR: This review has focused on linking this large body of literature on reactive oxygen species generation and modulation to the clinical syndromes that predispose humans to atherosclerosis and its complications.
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Unraveling the biological roles of reactive oxygen species.
Michael P. Murphy,Arne Holmgren,Nils-Göran Larsson,Barry Halliwell,Christopher J. Chang,Balaraman Kalyanaraman,Sue Goo Rhee,Paul J. Thornalley,Linda Partridge,David Gems,Thomas Nyström,Vsevolod V. Belousov,Paul T. Schumacker,Christine C. Winterbourn +13 more
TL;DR: Significant progress is being made in addressing reactive oxygen species and oxidative damage in biological systems, and here is a survey of some recent developments.
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