Cross talk of nitric oxide, oxygen radicals, and superoxide dismutase regulates the energy metabolism and cell death and determines the fates of aerobic life

Although oxygen is required for the energy metabolism in aerobic organisms, it generates reactive oxygen and nitrogen species that impair a wide variety of biological molecules, including lipids, proteins, and DNA, thereby causing various diseases. Because mitochondria are the major site of free radical generation, they are highly enriched with enzymes, such as Mn-type superoxide dismutase in matrix, and antioxidants including GSH on both sides of inner membranes, thus minimizing oxidative stress in and around this organelle. We recently showed that a cross talk of nitric oxide and oxygen radicals regulates the circulation, energy metabolism, reproduction, and remodeling of cells during embryonic development, and functions as a major defense system against pathogens. The present work shows that Cu/Zn-type superoxide dismutase, which has been postulated for a long time to be a cytosolic enzyme, also localizes bound to inner membranes of mitochondria, thereby minimizing oxidative stress in and around this organelle, while mitochondrial association decreases markedly with the variant types of the enzyme found in patients with familial amyotrophic lateral sclerosis. We also report that a cross talk of nitric oxide, superoxide, and molecular oxygen cooperatively regulates the fates of pathogens and their hosts and that oxidative stress in and around mitochondria also determines cell death in the development of animals and tissue injury caused by anticancer agents by some carnitine-inhibitable mechanism.