[Investigation of a causal relationship between mtDNA mutations and a mitochondrial respiratory dysfunction in...

The mitochondrial theory of aging has been proposed, which suggests that the accumulations of multiple in mtDNA with age induce decreased mitochondrial respiratory function, ultimately leading to aging. This hypothesis is widely accepted because mtDNA mutator mice (Polg^mut/mut mice) with a homozygous proofreading-deficient mutation in Polg gene accumulate random point mutations in mtDNA, resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, the accurate mtDNA mutation frequency in Polg^mut/mut mice has remained unclear, and the causal relationship between accumulation of random point mutations in mtDNA and mitochondrial respiratory dysfunction in Polg^mut/mut mice has been debated. Then, we verified the exact mtDNA mutation frequency in Polg mice and experimentally varied mtDNA mutation frequency to test their correlation with mitochondrial respiratory activity. Our results showed that, regardless of mtDNA mutation frequency, mitochondrial respiratory activity was mildly reduced in Polg^+/mut mice with a heterozygous proof-reading deficient mutation in Polg and severely reduced Polg^mut/mut mice. Moreover, by varying mtDNA mutation frequency, some Polg^+/+ mice showed mtDNA mutation frequency equivalent to those of Polg^mut/mut mice, but mitochondrial respiratory function in Polg^+/+ mice was normal. These results suggest that a reduced mitochondrial function in Polg mice is correlated with Polg mutation rather than accumulation of random mutations in mtDNA. Thus, this study proposed the need to reconsider the hypothesis that accumulation of random mutations in mtDNA induces a decreased respiratory function, which form the core of the mitochondrial theory of aging.