Mitochondrial disease and mtDNA mutation

Protasoni and Zeviani (2021) set out why mtDNA disease differs from nuclear disease. In sexuate organisms only the mother can transmit mutant mtDNA to offspring. A cell carries multiple copies of mtDNA, not two, so the copies may all match (homoplasmy) or differ (heteroplasmy). They list inherited mutated copies, replication errors, oxidative stress and inefficient DNA repair as routes to mutation in a share of the copies⁴. They report that the proportion of mutant to wild-type DNA strongly affects how severe the disease becomes⁵.

Martínez and colleagues (2020) reviewed the link between inherited mitochondrial disease and diabetes. They state that diabetes is frequently seen in these patients, whether the defect lies in mtDNA or in nuclear genes. They name m.3243A>G, in the leucine tRNA gene MT-TL1, as the most common defect, and link it to maternally inherited mitochondrial diabetes and deafness (MIDD)³. They add that carriers showed reduced pancreatic insulin secretion, while changes in insulin resistance and glucose metabolism cannot be excluded³.

Wallace (2013) took up a concern attributed to Kimura: a high mtDNA mutation rate should build a genetic load that could destroy the species. Wallace called this unfounded. He argued that the ovary removes proto-oocytes with severe mtDNA mutations before ovulation, so these never add to the load¹. Mutations that only subtly alter energy metabolism still pass into the germline. In his view they give bioenergetic diversity that lets subpopulations adapt to somewhat different energetic environments².

Iorio and colleagues (2024) place mtDNA mutation in the setting of ageing. They write that mtDNA mutations and reactive oxygen species rise together during ageing, and that this worsens mitochondrial dysfunction⁶. Their account differs in emphasis from Wallace's. Wallace stresses the variation that mutations supply, and Iorio and colleagues stress the damage they add with age²⁶.