Fiskum Gary, Starkov Anatoly, Polster Brian M, Chinopoulos Christos
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Ann N Y Acad Sci. 2003 Jun;991:111-9. doi: 10.1111/j.1749-6632.2003.tb07469.x.
Mitochondrial dysfunction, due to either environmental or genetic factors, can result in excessive production of reactive oxygen species, triggering the apoptotic death of dopaminergic cells in Parkinson's disease. Mitochondrial free radical production is promoted by the inhibition of electron transport at any point distal to the sites of superoxide production. Neurotoxins that induce parkinsonian neuropathology, such as MPP(+) and rotenone, stimulate superoxide production at complex I of the electron transport chain and also stimulate free radical production at proximal redox sites including mitochondrial matrix dehydrogenases. The oxidative stress caused by elevated mitochondrial production of reactive oxygen species promotes the expression and (or) intracellular distribution of the proapoptotic protein Bax to the mitochondrial outer membrane. Interactions between Bax and BH3 death domain proteins such as tBid result in Bax membrane integration, oligomerization, and permeabilization of the outer membrane to intermembrane proteins such as cytochrome c. Once released into the cytosol, cytochrome c together with other proteins activates the caspase cascade of protease activities that mediate the biochemical and morphological alterations characteristic of apoptosis. In addition, loss of mitochondrial cytochrome c stimulates mitochondrial free radical production, further promoting cell death pathways. Excessive mitochondrial Ca(2+) accumulation can also release cytochrome c and promote superoxide production through a mechanism distinctly different from that of Bax. Ca(2+) activates a mitochondrial inner membrane permeability transition causing osmotic swelling, rupture of the outer membrane, and complete loss of mitochondrial structural and functional integrity. While amphiphilic cations, such as dibucaine and propranolol, inhibit Bax-mediated cytochrome c release, transient receptor potential channel inhibitors inhibit mitochondrial swelling and cytochrome c release induced by the inner membrane permeability transition. These advances in the knowledge of mitochondrial cell death mechanisms and their inhibitors may lead to neuroprotective interventions applicable to Parkinsons's disease.
由于环境或遗传因素导致的线粒体功能障碍，可导致活性氧过量产生，引发帕金森病中多巴胺能细胞的凋亡死亡。在超氧化物产生位点远端的任何一点抑制电子传递，都会促进线粒体自由基的产生。诱导帕金森病神经病理学的神经毒素，如MPP(+)和鱼藤酮，会刺激电子传递链复合体I处的超氧化物产生，也会刺激包括线粒体基质脱氢酶在内的近端氧化还原位点的自由基产生。线粒体活性氧产生增加所引起的氧化应激，会促进促凋亡蛋白Bax在外膜的表达和（或）细胞内分布。Bax与BH3死亡结构域蛋白（如tBid）之间的相互作用，导致Bax整合到膜上、寡聚化，并使外膜对细胞色素c等膜间蛋白通透。一旦释放到细胞质中，细胞色素c与其他蛋白一起激活半胱天冬酶级联蛋白酶活性，介导凋亡特有的生化和形态学改变。此外，线粒体细胞色素c的丧失会刺激线粒体自由基产生，进一步促进细胞死亡途径。线粒体Ca(2+)过度积累也可通过一种与Bax明显不同的机制释放细胞色素c并促进超氧化物产生。Ca(2+)激活线粒体内膜通透性转变，导致渗透性肿胀、外膜破裂，以及线粒体结构和功能完整性的完全丧失。虽然两亲性阳离子，如丁卡因和普萘洛尔，可抑制Bax介导的细胞色素c释放，但瞬时受体电位通道抑制剂可抑制内膜通透性转变诱导的线粒体肿胀和细胞色素c释放。线粒体细胞死亡机制及其抑制剂方面的这些知识进展，可能会带来适用于帕金森病的神经保护干预措施。
