Abstract

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. In addition to anatomy, life requires energy and about 90% of energy comes from the mitochondrion. The mitochondrial genome consists thousands of copies of the maternally inherited mitochondrial DNA (mtDNA) plus between one and two thousand 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 materially inherited diseases. The milder mtDNA variants have accumulated sequentially along radiating material lineages as women spread throughout African and migrated out-of-Africa to colonize Eurasia and the Americas. A subset of the ancient mtDNA variants alter mitochondrial energy metabolism in ways that were beneficial in different regional environments. Lineages with these variants became enriched to generate regional groups of haplotypes, haplogroups. In alternative environments and/or with age these same adaptive variants can be maladaptive and increased the risk for disease. The rare tRNAGln nt A4336G variant defines a European lineage that is predisposed to Alzheimer and Parkinson Diseases. An ND1 T3394C (Y30H) variant increases the penetrance of Leber Hereditary Optic Atrophy (LHON) mutations, but is adaptive for high altitude in Tibetans. A homozygous frame shift mutation in the nDNA ADP /ATP translocase isoform 1 gene results in hypertrophic cardiomyopathy when combined with mtDNA haplogroup H but life-threatening heart disease when paired with mtDNA haplogroup U. The out-of-Africa macrohaplogroup N variants have been associated with breast cancer risk and can arise independently in other cancer cells. Mutations in the mtDNAs also accumulate with age in both stem and somatic tissue cells. These can be associated with various forms of cancer and also constitute the aging clock. The introduction of mtDNA variants into the mouse germline via female embryonic stem cells (mfESCs) has confirmed the causal role of mitochondrial deficiency in diseases. Mice harboring a COI T6859C V421A missense mutation develop a myopathy and cardiomyopathy. Mice harboring a ND6 G13997A P25A missense mutation develop a LHON -like optic neuropathy. Simply mixing two normal mtDNAs from 129 and NZB mice within the same cytoplasm causes marked neuropsychiatric symptoms and learning defects. Hence, the pathophysiology of the common diseases may be bioenergetic dysfunction and the genetic complexity of common diseases the result of the interaction of the thousands of nDNA and mtDNA bioenergetic gene variants.