Nitric oxide and mitochondrial respiration in the heart.
Nitric oxide (NO) inhibits the mitochondrial respiratory chain, resulting in inhibition of ATP production, increased oxidant production and increased susceptibility to cell death. NO reversibly binds to the oxygen binding site of cytochrome oxidase, reacting either with the oxidised copper to give inhibitory nitrite, or with the reduced haem, resulting in reversible inhibition in competition with oxygen. Because of this competition, NO may sensitise tissues to hypoxia. NO, or derivative N(2)O(3) or S-nitrosothiols, may inactivate complex I by S-nitrosation. Peroxynitrite (ONOO(-)) inhibits mitochondrial respiration at multiple sites, and also causes mitochondrial permeability transition. Inhibition of mitochondrial respiration by NO and its derivatives stimulates production of reactive oxygen and nitrogen species by mitochondria, which have signalling roles in the heart, but may also contribute to cell death. In the heart, NO is produced by endothelial NO synthase (eNOS) in endothelium and caveolae of cardiomyocytes, by neuronal NO synthase (nNOS) in sarcoplasmic reticulum and possibly mitochondria, and under pathological situations by inducible NO synthase (iNOS) in the sarcoplasm. Haemoglobin and myoglobin may have multiple roles in determining oxygen and NO gradients within the heart, which may remove NO at high oxygen, but possibly supply it at low oxygen. Stimulating or inhibiting NOS in the heart has been found to cause small changes in heart oxygen consumption in vivo; however, it is still unclear whether these changes are due to direct NO inhibition of mitochondrial respiration or indirect actions of NO. NO inhibition of mitochondrial respiration is likely to be more important in the heart during hypoxia and/or pathologies where iNOS is expressed.
Brown
Guy C
GC
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK. gcb@mole.bio.cam.ac.uk
Borutaite
Vilmante
V
D000818:Animals; D006331:Heart Diseases / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology*
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase