Reactive Oxygen and Nitrogen Species Regulate Mitochondrial Ca²⁺ Homeostasis and Respiration

Abstract

The reduction of molecular oxygen to water provides most of the biologically useful energy. However, oxygen reduction is a mixed blessing because incompletely reduced oxygen species such as superoxide or peroxides are quite reactive and can, when out of control, cause damage. In mitochondria, where most of the oxygen utilized by eukaryotic cells is reduced, the dichotomy of oxygen shows itself best. Thus, reactive oxygen is a threat to them, as is evident from oxidative damage to mitochondrial lipids, proteins, and nucleic acids. Reactive oxygen, in the form of peroxides, also serves useful functions in mitochondria. This is exemplified by the control of mitochondrial and cellular calcium homeostasis, whose understanding has improved greatly during the last few years. An exciting new aspect is the discovery that nitric oxide and congeners have an enormous impact on mitochondria. Physiological concentrations of nitrogen monoxide (NO) at physiological cellular oxygen pressure inhibit cytochrome oxidase and thereby respiration. A transient inhibition of cytochrome oxidase by NO appears to be used in at least some forms of cell signalling. Peroxynitrite, the product of the reaction between superoxide and NO, can stimulate the specific calcium release pathway from mitochondria by oxidizing some vicinal thiols in mitochondria. There is evidence mounting that mitochondrial calcium handling and its modulation by reactive oxygen and nitrogen species is important for necrotic and apoptotic cell death.