title: Mitochondrial DNA mutations, apoptosis, and the misfolded protein response.
abstract: Studies of transgenic mice with accelerated accumulation of mtDNA mutations specifically in the heart lead us to propose that apoptotic signaling and cell death is central to the pathogenesis of mtDNA mutations in aging. It is the cellular response to that apoptotic signaling and the organ?s compensatory response to a loss of cells that specify the phenotype of an accumulation of mtDNA mutations. In the heart, cardiomyocytes induce a vigorous anti-apoptotic, pro-survival response to counteract mitochondrial apoptotic signaling. The heart up-regulates contractility of remaining myocytes in order to maintain cardiac output. We hypothesize that mutant mitochondrial proteins originate apoptotic signaling by interacting with proteins already in place in the mitochondrial outer membrane that regulate apoptosis, for example the pro-apoptotic protein Bak. Since it is unlikely that all mutant mitochondrial proteins have the necessary structure and localization within the inner membrane to activate Bak appropriately, only a small fraction of an age-associated burden of mtDNA mutations may be pathogenic. In this model, reactive oxygen species generated by mitochondrial respiration drive the formation of mtDNA mutations, but are not the primary mechanism for their pathogenicity.
authors.affiliation: Department of Molecular Microbiology and Immunology, St. Louis University Health Science Center, Missouri, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Mott
authors.forename: Dekui
authors.initials: D
authors.lastname: Zhang
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Zassenhaus
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017510:Protein Folding
chemical_list: D004272:DNA, Mitochondrial