Adam-Vizi Vera
Department of Medical Biochemistry, Semmelweis University, Neurochemical Group, Hungarian Academy of Sciences, Budapest, Hungary.
Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1140-9. doi: 10.1089/ars.2005.7.1140.
Overwhelming evidence has accumulated indicating that oxidative stress is a crucial factor in the pathogenesis of neurodegenerative diseases. The major site of production of superoxide, the primary reactive oxygen species (ROS), is considered to be the respiratory chain in the mitochondria, but the exact mechanism and the precise location of the physiologically relevant ROS generation within the respiratory chain have not been disclosed as yet. Studies performed with isolated mitochondria have located ROS generation on complex I and complex III, respectively, depending on the substrates or inhibitors used to fuel or inhibit respiration. A more "physiological" approach is to address ROS generation of in situ mitochondria, which are present in their normal cytosolic environment. Hydrogen peroxide formation in mitochondria in situ in isolated nerve terminals is enhanced when complex I, complex III, or complex IV is inhibited. However, to induce a significant increase in ROS production, complex III and complex IV have to be inhibited by >70%, which raises doubts as to the physiological importance of ROS generation by these complexes. In contrast, complex I inhibition to a small degree is sufficient to enhance ROS generation, indicating that inhibition of complex I by approximately 25-30% observed in postmortem samples of substantia nigra from patients suffering from Parkinson's disease could be important in inducing oxidative stress. Recently, it has been described that a key Krebs cycle enzyme, alpha-ketoglutarate dehydrogenase (alpha-KGDH), is also able to produce ROS. ROS formation by alpha-KGDH is regulated by the NADH/NAD+ ratio, suggesting that this enzyme could substantially contribute to generation of oxidative stress due to inhibition of complex I. As alpha-KGDH is not only a generator but also a target of ROS, it is proposed that alpha-KGDH is a key factor in a vicious cycle by which oxidative stress is induced and promoted in nerve terminals.
越来越多的确凿证据表明，氧化应激是神经退行性疾病发病机制中的一个关键因素。超氧化物作为主要的活性氧（ROS），其主要产生部位被认为是线粒体中的呼吸链，但呼吸链内生理相关ROS产生的确切机制和精确位置尚未明确。使用分离的线粒体进行的研究表明，根据用于驱动或抑制呼吸的底物或抑制剂不同，ROS分别在线粒体复合物I和复合物III上产生。一种更“生理”的方法是研究原位线粒体（即处于正常细胞质环境中的线粒体）的ROS产生情况。当复合物I、复合物III或复合物IV受到抑制时，分离的神经末梢中原位线粒体中的过氧化氢生成会增加。然而，要使ROS产生显著增加，复合物III和复合物IV必须被抑制>70%，这让人质疑这些复合物产生ROS的生理重要性。相比之下，对复合物I进行小程度的抑制就足以增强ROS的产生，这表明在帕金森病患者黑质的尸检样本中观察到的约25 - 30%的复合物I抑制可能在诱导氧化应激中起重要作用。最近，有研究表明关键的三羧酸循环酶α-酮戊二酸脱氢酶（α-KGDH）也能够产生ROS。α-KGDH产生ROS受NADH/NAD+比值调节，这表明该酶可能由于复合物I的抑制而在氧化应激的产生中起重要作用。由于α-KGDH不仅是ROS的产生者，也是ROS的作用靶点，因此有人提出α-KGDH是神经末梢中诱导和促进氧化应激的恶性循环中的关键因素。
