Brown G C
Department of Biochemistry, University of Cambridge, UK.
Mol Cell Biochem. 1997 Sep;174(1-2):189-92.
Nitric oxide (NO) at high levels is cytotoxic, and may be involved in a range of inflammatory, neurodegenerative, and cardiovascular/ischaemic pathologies. The mechanism of NO-induced cytotoxicity is unclear. Recently we and others have found that low (nanomolar) levels of NO reversibly inhibit mitochondrial respiration by binding to the oxygen binding site of cytochrome oxidase in competition with oxygen. This raises the apparent K(m) for oxygen of mitochondrial respiration into the physiological range, potentially making respiration sensitive to the oxygen level. The NO inhibition of oxygen consumption was seen in isolated cytochrome oxidase, mitochondria, brain nerve terminals, and cultured cells. Cultured astrocytes activated to express the inducible from of NO synthase produced up to 1 microM NO and strongly inhibited their own cellular respiration rate. This respiratory inhibition was rapidly reversed by removing the NO, and was due to the inhibition of cytochrome oxidase. These results suggest that any cell producing high levels of NO will inhibit its own respiration and that of surrounding cells, and make the respiration rate sensitive to the oxygen level. This inhibition of energy metabolism may contribute to cytotoxicity or cytostasis in some pathologies.
高水平的一氧化氮（NO）具有细胞毒性，可能参与一系列炎症、神经退行性病变以及心血管/缺血性疾病。NO诱导细胞毒性的机制尚不清楚。最近，我们和其他人发现低水平（纳摩尔级）的NO通过与细胞色素氧化酶的氧结合位点结合，与氧竞争，从而可逆地抑制线粒体呼吸。这使得线粒体呼吸对氧的表观米氏常数（K(m)）升高到生理范围内，可能使呼吸对氧水平敏感。在分离的细胞色素氧化酶、线粒体、脑神经末梢和培养细胞中都观察到了NO对氧消耗的抑制作用。被激活以表达诱导型一氧化氮合酶的培养星形胶质细胞可产生高达1微摩尔的NO，并强烈抑制其自身的细胞呼吸速率。去除NO后，这种呼吸抑制作用迅速逆转，这是由于细胞色素氧化酶受到抑制。这些结果表明，任何产生高水平NO的细胞都会抑制其自身以及周围细胞的呼吸，并使呼吸速率对氧水平敏感。这种能量代谢的抑制可能在某些疾病中导致细胞毒性或细胞生长停滞。
