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Journal Article

Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice

MPS-Authors

Edgar,  Daniel
Max Planck Society;

Shabalina,  Irina
Max Planck Society;

Camara,  Yolanda
Max Planck Society;

Wredenberg,  Anna
Max Planck Society;

Calvaruso,  Maria Antonietta
Max Planck Society;

Nijtmans,  Leo
Max Planck Society;

Nedergaard,  Jan
Max Planck Society;

Cannon,  Barbara
Max Planck Society;

Larsson,  Nils-Göran
Max Planck Society;

Trifunovic,  Aleksandra
Max Planck Society;

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Citation

Edgar, D., Shabalina, I., Camara, Y., Wredenberg, A., Calvaruso, M. A., Nijtmans, L., et al. (2009). Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab, 10(2), 131-138.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0028-58CC-3
Abstract
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.