A Mitochondrial Etiology of Metabolic and Degenerative Diseases, Cancer and Aging
National Institutes of Health
For half a millennium Western medicine has focused on anatomy and for the past century on nuclear DNA (nDNA), Mendelian, genetics. While these concepts have permitted many biomedical advances, they have proven insufficient for understanding the common “complex” diseases. Life requires energy, 90 percent of which comes from the mitochondrion. The mitochondrial genome consists of thousands of copies of the maternally inherited mitochondrial DNA (mtDNA) plus 1,000–2,000 nDNA genes. The mtDNA has a very high mutation rate, but the most deleterious mutations are removed by an ovarian prefertilization selection system. Hence, functional mtDNA variants are constantly being introduced into the human population, the more deleterious resulting in recent maternally inherited diseases. The milder mtDNA variants have accumulated sequentially as women spread throughout Africa and migrated out to colonize Eurasia and the Americas. Some ancient mtDNA variants alter mitochondrial energy metabolism in ways that were beneficial in different regional environments. In alternative environments and/or with age these same adaptive variants can be maladaptive and increase the risk for disease. For example, one variant increases the penetrance of mutations associated with an inherited form of vision loss, but is adaptive for survival at high altitudes. Mutations in the mtDNAs also accumulate with age in both stem and somatic tissue cells and can be associated with various forms of cancer. The introduction of mtDNA variants into the mouse germline via female embryonic stem cells has confirmed the causal role of mitochondrial deficiency in diseases. Hence, the pathophysiology of some common diseases may be bioenergetic dysfunction and their genetic complexity the result of thousands of nDNA and mtDNA bioenergetic gene variants interacting.
Webinar Type: Recorded