Mitochondrial Free Radical Production, Antioxidant Defenses and Cell Signaling

Abstract

Mitochondria were classically recognized as the organelles that produce the energy required to drive the endergonic processes of cell life, but now they are considered as the most important cellular source of free radicals, as the main target for free radical regulatory and toxic actions, and as the source of signaling molecules that command cell cycle, proliferation, and apoptosis. Mitochondrial production of the primary free radicals superoxide anion (O₂^⋅–) and nitric oxide (NO), as well as of the termination products H₂O₂ (hydrogen peroxide) and peroxynitrite (ONOO^–), is described. A specialized network of intramitochondrial antioxidants consisting of the enzymes Mn-superoxide dismutase and glutathione peroxidase and of the reductants NADH2, ubiquinol and reduced glutathione, appears operative in minimizing the potentially harmful effects of O₂^⋅–, NO, H₂O₂ and ONOO^–. The effective operation of the intramitochondrial network of antioxidants is necessary to prevent the oxidant-driven mitochondrial damage that leads to mitochondrial dysfunction, a syndrome recognized in several diseases, inflammation, and aging. Deficiency in nutritional antioxidants and environmental metal toxicity are considered in relation to mitochondrial oxidative stress and dysfunction. Parkinson’s and Alzheimer’s diseases have been claimed to be associated with neuronal and systemic oxidative stress. There are reports on the beneficial effects of vitamins and antioxidants for the treatment of both diseases. Nitric oxide and H₂O₂ participate in the cell signaling that commands cell cycle, proliferation, and apoptosis. A mechanism involving mitogen-activated protein kinases is described. The role of mitochondria in apoptosis is well established through the mitochondrion-dependent pathway of cell death, which includes increased NO production, loss of membrane potential, appearance of dysfunctional mitochondria, cytochrome c release, and opening of the outer membrane voltage-dependent anion channel.