A Mitochondrial Etiology of Metabolic and Degenerative Diseases, Cancer and Aging

The Western medical emphasis on anatomy and nuclear DNA (nDNA) genetics has failed to provide adequate explanations for the common “complex” diseases. In addition to anatomy, life requires energy and most energy comes from the mitochondrion whose genome encompasses 1000s of maternally inherited mitochondrial DNAs (mtDNA) plus 1000-2000 nDNA genes. The mtDNA has a high mutation rate and recent mtDNA mutations have been linked to a wide range of common disease phenotypes. As women migrated out-of-Africa and around the globe mutations in the mtDNA also accumulated along radiating material lineages resulting regional mtDNA haplogroups.  Many of these ancient mtDNA variants permitted human energetic adaptation to regional environments but today can predisposition to common diseases.  Mutations accumulate in somatic tissue mtDNAs with age providing the aging clock and certain nDNA and mtDNA mitochondrial gene variants when combined can result in disease.  The mitochondrial etiology of common diseases has been confirmed by introducing nDNA and mtDNA mitochondrial gene mutations into the mouse resulting in the recapitulation of common disease phenotypes. Mice harboring the mtDNA COI T6859C V421A and ND6 G13997A P25A missense mutations develop myopathy plus cardiomyopathy and neurodegenerative disease, respectively.  Combining nDNA and mtDNA mutations can markedly exacerbate their phenotypes and simply mixing two normal but different mouse mtDNAs can result in neuropsychiatric symptoms. Hence, pathophysiological basis of common diseases is bioenergetic dysfunction and their genetic complexity is the result of the adverse interaction of thousands of nDNA and mtDNA bioenergetic gene variants.