Mitochondrial free radical production and cell signaling.

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. The progress in the knowledge of mitochondrial functions in the last decades is reviewed. The mitochondrial production of the primary free radicals superoxide anion (O(2)(-)) and nitric oxide (NO), as well as of the termination products H(2)O(2) (hydrogen peroxide) and peroxynitrite (ONOO(-)), is described. A network of intramitochondrial antioxidants consisting of the enzymes Mn-superoxide dismutase and glutathione peroxidase and of the reductants NADH(2), ubiquinol and reduced glutathione, is operative in minimizing the potentially harmful effects of O(2)(-), NO, H(2)O(2) and ONOO(-). Nitric oxide and H(2)O(2) participate in cell signaling, through narrow concentration ranges that signal for opposite cellular situations, i.e., proliferation or apoptosis. A mechanism involving mitogen-activated protein kinases is described. The role of mitochondria in apoptosis is well established through the mitochondrion-dependent pathways of cell death, that includes increased NO production, loss of membrane potential, appearance of dysfunctional mitochondria, cytochrome c release and opening of the voltage-dependent anion channel of the outer membrane.