Free Radical Pathophysiology

VALDEZ LB; ZAOBORNYJ T; BOMBICINO S; GONZALEZ GF; BOVERIS A

Physiological regulation of heart mitochondrial nitric oxide synthase

Transworld Research Network

Lugar: Kerala, India; Año: 2007;

Heart submitochondrial membranes produce NO at a rate of 2.19 ± 0.10 nmol NO/min.mg protein. The production of NO has been observed not only in mitochondrial membranes but also in coupled mitochondria, being NO release 40% lower in state 3 than in state 4. Heart mitochondrial NO production accounts for about 60% of total cellular NO generation, suggesting a central regulatory role of mitochondrial NO in cardiomyocytes. Mitochondrial NOS is a highly regulated enzyme, which in turn, plays a regulatory role through the establishment of mitochondrial NO steady state levels, that modulate O2 uptake and O2- and H2O2 production rates. At 50-200 nM concentrations, NO exhibits two main effects on the mitochondrial respiratory chain: the competitive inhibition of cytochrome oxidase and the stimulation of O2- production by inhibition of electron transfer at complex III. The ability of mtNOS activity to modulate mitochondrial O2 uptake and H2O2 production, by its product NO, is termed mtNOS functional activity, and is considered the main pathway by which NO exerts its role as an intracellular regulator in physiological, pathological and pharmacological conditions. Changes in mtNOS functional activity reflect variations in mitochondrial NO production and NO steady state concentrations. Biological situations in which the regulation of mitochondrial respiration by NO are considered important are hypoxia, ischemia-reperfusion, hypothyroidism, inflammation, apoptosis and aging.