Brown Guy C, Borutaite Vilmante
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK.
Cardiovasc Res. 2007 Jul 15;75(2):283-90. doi: 10.1016/j.cardiores.2007.03.022. Epub 2007 Apr 3.
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.
一氧化氮（NO）抑制线粒体呼吸链，导致ATP生成受抑、氧化剂生成增加以及细胞死亡易感性增强。NO可逆性地结合到细胞色素氧化酶的氧结合位点，要么与氧化态的铜反应生成抑制性亚硝酸盐，要么与还原态的血红素反应，从而在与氧的竞争中导致可逆性抑制。由于这种竞争，NO可能使组织对缺氧敏感。NO或其衍生物N(2)O(3)或S-亚硝基硫醇可能通过S-亚硝基化使复合体I失活。过氧亚硝酸盐（ONOO(-)）在多个位点抑制线粒体呼吸，还会导致线粒体通透性转换。NO及其衍生物对线粒体呼吸的抑制会刺激线粒体产生活性氧和氮物质，这些物质在心脏中具有信号传导作用，但也可能导致细胞死亡。在心脏中，NO由内皮细胞和心肌细胞小窝中的内皮型一氧化氮合酶（eNOS）、肌浆网以及可能的线粒体中的神经元型一氧化氮合酶（nNOS）产生，在病理情况下则由肌浆中的诱导型一氧化氮合酶（iNOS）产生。血红蛋白和肌红蛋白在决定心脏内氧和NO梯度方面可能具有多种作用，在高氧时可能清除NO，但在低氧时可能提供NO。已发现刺激或抑制心脏中的一氧化氮合酶会在体内引起心脏氧消耗的微小变化；然而，尚不清楚这些变化是由于NO对线粒体呼吸的直接抑制还是NO的间接作用。在缺氧和/或iNOS表达的病理情况下，NO对线粒体呼吸的抑制在心脏中可能更为重要。
