Sarti Paolo, Forte Elena, Mastronicola Daniela, Giuffrè Alessandro, Arese Marzia
Department of Biochemical Sciences, Sapienza University of Rome, Italy.
Biochim Biophys Acta. 2012 Apr;1817(4):610-9. doi: 10.1016/j.bbabio.2011.09.002. Epub 2011 Sep 14.
The reactions between Complex IV (cytochrome c oxidase, CcOX) and nitric oxide (NO) were described in the early 60's. The perception, however, that NO could be responsible for physiological or pathological effects, including those on mitochondria, lags behind the 80's, when the identity of the endothelial derived relaxing factor (EDRF) and NO synthesis by the NO synthases were discovered. NO controls mitochondrial respiration, and cytotoxic as well as cytoprotective effects have been described. The depression of OXPHOS ATP synthesis has been observed, attributed to the inhibition of mitochondrial Complex I and IV particularly, found responsible of major effects.
The review is focused on CcOX and NO with some hints about pathophysiological implications. The reactions of interest are reviewed, with special attention to the molecular mechanisms underlying the effects of NO observed on cytochrome c oxidase, particularly during turnover with oxygen and reductants.
The NO inhibition of CcOX is rapid and reversible and may occur in competition with oxygen. Inhibition takes place following two pathways leading to formation of either a relatively stable nitrosyl-derivative (CcOX-NO) of the enzyme reduced, or a more labile nitrite-derivative (CcOX-NO(2)(-)) of the enzyme oxidized, and during turnover. The pathway that prevails depends on the turnover conditions and concentration of NO and physiological substrates, cytochrome c and O(2). All evidence suggests that these parameters are crucial in determining the CcOX vs NO reaction pathway prevailing in vivo, with interesting physiological and pathological consequences for cells.
早在20世纪60年代就有关于复合物IV（细胞色素c氧化酶，CcOX）与一氧化氮（NO）之间反应的描述。然而，认为NO可能导致生理或病理效应，包括对线粒体的效应的认识，直到20世纪80年代发现内皮源性舒张因子（EDRF）的身份以及一氧化氮合酶合成NO之后才出现。NO控制线粒体呼吸，并且已经描述了其细胞毒性和细胞保护作用。已经观察到氧化磷酸化ATP合成的抑制，这尤其归因于线粒体复合物I和IV的抑制，发现它们是主要效应的原因。
本综述聚焦于CcOX和NO，并对病理生理意义给出一些提示。对感兴趣的反应进行了综述，特别关注了在细胞色素c氧化酶上观察到的NO效应的分子机制，尤其是在与氧气和还原剂周转期间。
NO对CcOX的抑制迅速且可逆，可能与氧气竞争发生。抑制通过两条途径发生，导致形成酶还原态的相对稳定的亚硝酰衍生物（CcOX-NO）或酶氧化态的更不稳定的亚硝酸盐衍生物（CcOX-NO₂⁻），并且发生在周转过程中。占主导的途径取决于周转条件、NO和生理底物细胞色素c以及O₂的浓度。所有证据表明，这些参数对于确定体内占主导的CcOX与NO反应途径至关重要，对细胞具有有趣的生理和病理后果。
