Radi R, Rodriguez M, Castro L, Telleri R
Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Arch Biochem Biophys. 1994 Jan;308(1):89-95. doi: 10.1006/abbi.1994.1013.
Mammalian mitochondria are sensitive targets of the cytotoxic effects of superoxide (O.2-) and nitric oxide (.NO). In turn, when superoxide and nitric oxide are simultaneously produced, they rapidly react with each other yielding the highly oxidizing peroxynitrite anion (ONOO-) which may be also toxic to mammalian mitochondria. In this study we report that peroxynitrite exposure to rat heart mitochondria resulted in significant inactivation of electron carriers such as succinate dehydrogenase and NADH dehydrogenase as well as the mitochondrial ATPase. As a result of enzyme inactivation, peroxynitrite lead to a profound inhibition of glutamate/malate- and succinate-supported oxygen consumption but did not cause mitochondrial uncoupling. Secondary to inhibiting mitochondrial electron transport, peroxynitrite induced an enhanced succinate-stimulated hydrogen peroxide formation by heart mitochondria. Most of the damaging effects against mitochondria can be ascribed to peroxynitrite anion itself and not to hydroxyl radical-like oxidant yielded during the proton-catalyzed decomposition of peroxynitrite, as hydroxyl radical scavengers provided a rather modest protection. Our observations indicate that mitochondria may constitute a key intracellular loci for the toxic effects of peroxynitrite under the various pathological conditions in which peroxynitrite appears to play a contributory role.
哺乳动物线粒体是超氧化物（O₂⁻）和一氧化氮（·NO）细胞毒性作用的敏感靶点。反过来，当超氧化物和一氧化氮同时产生时，它们会迅速相互反应，生成具有高度氧化性的过氧亚硝酸根阴离子（ONOO⁻），这对哺乳动物线粒体也可能有毒性。在本研究中，我们报告了过氧亚硝酸根作用于大鼠心脏线粒体导致电子载体如琥珀酸脱氢酶和NADH脱氢酶以及线粒体ATP酶显著失活。由于酶失活，过氧亚硝酸根导致谷氨酸/苹果酸和琥珀酸支持的氧消耗受到严重抑制，但未引起线粒体解偶联。继发于抑制线粒体电子传递，过氧亚硝酸根诱导心脏线粒体琥珀酸刺激的过氧化氢生成增加。对线粒体的大多数损伤作用可归因于过氧亚硝酸根阴离子本身，而非过氧亚硝酸根质子催化分解过程中产生的类似羟基自由基的氧化剂，因为羟基自由基清除剂提供的保护作用相当有限。我们的观察结果表明，在过氧亚硝酸根似乎起作用的各种病理条件下，线粒体可能是过氧亚硝酸根毒性作用的关键细胞内位点。
