The mtDNA mutator mouse: Dissecting mitochondrial involvement in aging

Abstract

The role of mtDNA mutations in aging has been intensely debated because of their low abundance and correlative connection with aging. The creation of mtDNA mutator mice provided the first evidence that somatic mtDNA mutations have the capacity to cause a variety of aging phenotypes in mammals, and they do so without inducing ROS production or increasing oxidative stress. We have recently provided evidence that the accumulation of point mutations in mtDNA leads to the synthesis of respiratory chain subunits with amino acid substitutions that impair complex stability in mtDNA mutator mice. Furthermore, we have demonstrated that the point mutations cause progressive respiratory chain deficiency, which, we propose, leads to premature aging. These results have been challenged by another group working on a similar model, who argues that the point mutations in mtDNA we found at very high levels in mtDNA mutator mice do not cause the phenotype. Instead, they argue that circular mtDNA molecules with large deletions, are the culprit. This intense debate about molecular mechanism of mitochondrial dysfunction that is causing progeroid phenotypes in the mtDNA mutator mice is the main topic of this research perspective.

Keywords: mtDNA deletions; mtDNA mutator mice; mtDNA point mutations; oxidative deficiency; premature aging.