Mitochondrial energy production and its reaction to the pathophysiology of disease. Five features of mitochondrial metabolism are central to the pathophysiology of the common age-related diseases: (1) energy production by OXPHOS; (2) regulation of cellular oxidation–reduction (redox) state; (3) ROS generation as a by-product of OXPHOS; (4) buffering of the cytosolic and mitochondrial Ca2+ levels; and (5) regulation of apoptosis through activation of the mtPTP. ADP or ATP, adenosine di- or triphosphate, ANT, adenine nucleotide translocator; cytc, cytochrome c; GPx, glutathione peroxidase-1; LDH, lactate dehydrogenase; MnSOD, manganese superoxide dismutase or SOD2; NADH, reduced nicotinamide adenine dinucleotide; TCA, tricarboxylic acid cycle; VDAC, voltage-dependent anion channel; I, II, III, IV, and V, OXPHOS complexes I–V. Complex I is composed of 45 polypeptides, seven (ND1, 2, 3, 4L, 4, 5, 6) encoded by the mammalian mtDNA; complex II consists of four nDNA-encoded polypeptides; complex III consists of 11 polypeptides, one (cytb) encoded by the mtDNA; complex IV is composed of 13 polypeptides, three (COI, II, III) encoded by the mtDNA; and complex V is composed of ~15 polypeptides, two (ATP6, 8) encoded by the mtDNA. (Modified from Wallace 2005, 2007; Ruiz-Pesini et al. 2007.)