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Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice.
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
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2009 (English)In: Cell metabolism, ISSN 1932-7420, Vol. 10, no 2, 131-8 p.Article in journal (Refereed) Published
Abstract [en]

The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain function. We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts. These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits. Our findings reveal a mechanism for induction of aging phenotypes by demonstrating a causative role for amino acid substitutions in mtDNA-encoded respiratory chain subunits, which, in turn, leads to decreased stability of the respiratory chain complexes and respiratory chain deficiency.

Place, publisher, year, edition, pages
2009. Vol. 10, no 2, 131-8 p.
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Physiology
Research subject
Physiology
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URN: urn:nbn:se:su:diva-32931DOI: 10.1016/j.cmet.2009.06.010ISI: 000268711200010PubMedID: 19656491OAI: oai:DiVA.org:su-32931DiVA: diva2:281990
Available from: 2009-12-18 Created: 2009-12-18 Last updated: 2011-07-12Bibliographically approved

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