Mitochondrial OXPHOS can be perturbed by nDNA genetic alterations and/or epigenomic regulation, by mtDNA ancient adaptive of recent deleterious mutations, or by variation in the availability of calories and in caloric demands. Alterations in mitochondrial structure and function can impair OXPHOS, which in turn can reduce energy production, alter cellular redox state, increase ROS production, deregulate Ca²⁺ homeostasis, and ultimately activate the mtPTP, leading to apoptosis. These and other consequences of OXPHOS perturbation can destabilize mtDNA. This results in progressive accumulation of somatic mtDNA mutations and decline of mitochondrial function, which accounts for aging and the delayed-onset and progressive course of degenerative diseases. As energy output declines, the most energetic tissues are preferentially affected, resulting in degenerative diseases of the central nervous system, heart, muscle, and kidney. Aberrant mitochondrial caloric metabolism also leads to metabolic deregulation, endocrine dysfunction, and symptoms such as diabetes, obesity, and cardiovascular disease. The release into the blood stream of mtDNA mutant N-formylmethionine polypeptides plus the mtDNA can initiate the inflammatory response, contributing to autoimmune diseases (e.g., multiple sclerosis and type I diabetes) and possibly also to the inflammatory component of late-onset degenerative diseases. Finally, cancer cells must manage energy resources to permit rapid replication (95). Figure adapted with permission from Cold Spring Harbor Press (55).