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ited mtDNA. This requires that each new mutation be tested by natural selection in the context of the previously existing variants encoded by that mtDNA (Wallace, 2007).

mtDNA Variation in Adaptation and Disease

Because each cell has hundreds of mitochondria and thousands mtDNAs, new mtDNA mutations generate an intracellular mixture of mutant and normal mtDNAs, heteroplasmy. The percentage of mutant and normal mtDNAs can be unequally distributed at cytokinesis, such that the percentage of mutant mtDNAs can drift during successive mitotic and meiotic cell divisions, replicative segregation.

As the percentage of deleterious mtDNA mutations increases, the energy output of the cell declines until it drops below the minimum energy output required for that cell type to function and symptoms ensue, the bioenergetic threshold. To date, more than 200 pathogenic mtDNA mutations have been identified, and these cause all of the symptoms seen in the common metabolic and degenerative diseases including diabetes and metabolic syndrome, forms of blindness, deafness, neurodegenerative disease, myopathy, cardiomyopathy, renal dysfunction, and hepatic failure. Mutations in the mtDNA also contribute to cancer and aging (Wallace, 2005, 2007).

The high mtDNA mutation rate means that deleterious mtDNA mutations are very common. The frequency of recognized mitochondrial diseases is already estimated at 1/4,000–1/5,000 (Schaefer et al., 2008), and the de novo mtDNA mutation rate observed in cord blood, as assessed through 15 known pathogenic mutations, has been reported as 1 in 200 (Elliott et al., 2008). Given the high mtDNA mutation rate and the great importance and conservation of the mtDNA genes, the cumulative mtDNA genetic load should drive animal species to extinction. This paradox is resolved because the mammalian ovary encompasses a selective system that systematically eliminates those proto-oocyes that harbor the most severely deleterious mtDNA mutations (Fan et al., 2008; Stewart et al., 2008). Consequently, only oocytes with mildly deleterious, neutral, or beneficial mtDNA variants are ovulated and can be transmitted into the next generation. New mtDNA variants are constantly being introduced into animal populations, thus modifying individual energy metabolism. These variants provide the physiological variability required for subpopulations to adjust to new regional energetic environments.

As an mtDNA harboring an adaptive mutation becomes enriched in a new energy environment, additional neutral or advantageous mtDNA mutations accumulate sequentially along that regional maternal lineage. This creates distinctive branches of the mtDNA tree, each a cluster of

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