Random Point Mutations with Major Effects on Protein-Coding Genes Are the Driving Force behind Premature Aging in mtDNA Mutator Mice

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.

Mitochondrial DNA mutations in disease and aging

“…However, this study has been refuted in several independent studies, in which sensitive PCR assays (Edgar et al, 2009;Kraytsberg et al, 2009) or deep sequencing (Williams et al, 2010;Ameur et al, 2011) could not detect any significant levels of circular mtDNA molecules with deletions in various tissues of mtDNA mutator mice. In addition, the biochemical phenotype in mtDNA mutator mice is fully consistent with the idea that point mutations of mtDNA create amino acid substitutions of respiratory chain subunits, which explains the observed decline in the stability of the respiratory chain complexes (Edgar et al, 2009).…”

“…Mosaic respiratory chain deficiency caused by clonal expansion of mtDNA mutations is ubiquitously observed in human aging, but the extent to which this aberration impairs organ function is unknown. The mtDNA mutator mice (Table I) develop a premature aging syndrome, which is caused by the accumulation of point mutations and the presence of linear deleted mtDNA molecules, which likely represent a continuously formed replication intermediate (Trifunovic et al, 2004;Bailey et al, 2009;Edgar et al, 2009). There has been one study arguing that a third type of mutation, circular mtDNA molecules with deletions, drives the phenotype of mtDNA mutator mice (Vermulst et al, 2008).…”

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

“…Empiric evidence further supports the possibility that ageassociated increases in mtDNA mutation may drive aging-related phenotypes (66,144). Whether the responsible mtDNA mutations are point mutations or deletions is a topic of debate (29,64,154). Interestingly, humans with mtDNA polymerase gamma variants or mutations that could potentially accelerate mtDNA mutation accumulation can present with parkinsonism or Parkinsons's disease (26,48,71,72).…”

Preventive cytoprotection in social diseases

“…Их суть так или иначе сводится к уменьшению количества энергии, син-тезируемой митохондриями в кардиомиоцитах, последу-ющему кислородному голоданию, а также к гибели клеток и замещению их соединительно-тканным матриксом. Массовая гибель митохондрий и нарушение их функций проявляются патологией сердечной мышцы, уменьшени-ем роста и веса больных, снижением минеральной плот-ности костной ткани, появлением нарушений сердечного ритма, атрофией зрительного нерва, сахарным диабетом, низкой толерантностью к физической нагрузке, преждев-ременным старением, расстройствами психики, сосуди-стыми катастрофами [13].…”