Oxidative stress in mitochondria - Decision to survival and death of neurons in neurodegenerative disorders
Oxidative stress in mitochondria - Decision to survival and death of neurons in neurodegenerative disorders
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DOI：
10.1385/mn:31:1-3:081
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发表时间：
2005-01-01
影响因子：
5.1
通讯作者：
Tanaka, M
中科院分区：
文献类型：
--
作者：
Naoi, M;Maruyama, W;Tanaka, M
在线粒体中，通过单胺氧化酶的生物胺的氧化磷酸化和酶促氧化产生活性氧和氮物质，其被提出在神经退行性疾病（包括帕金森病和阿尔茨海默病）中引起神经元细胞死亡。在这些疾病中，线粒体功能障碍、氧化应激增加和氧化修饰蛋白的积累参与了确定神经元中的细胞死亡。这些因素之间的相互作用进行了研究，通过使用过氧亚硝基生成剂，N-吗啉代悉尼酮亚胺（SIN-1）和复合物1的抑制剂，鱼藤酮，在人多巴胺能SH-SY 5 Y细胞。在对照细胞中，过氧亚硝酸盐硝化蛋白质，特别是线粒体复合物I的亚基，作为3-硝基酪氨酸，这表明神经元暴露于恒定的氧化应激，即使在生理条件下。SIN-1和蛋白酶体抑制剂苄氧羰基-L-异亮氨酰-γ-叔丁基-L-丙氨酰-L-亮氨酸（PSI）显著增加硝化蛋白的水平，同时诱导细胞凋亡。鱼藤酮诱导线粒体功能障碍和丙烯醛修饰的蛋白质的积累和聚集，丙烯醛是细胞中脂质过氧化的醛产物。同时，蛋白酶体20 S β亚基的活性显著降低，从而降解氧化修饰的蛋白。SIN-1引起的氧化应激增加导致SH-SY 5 Y细胞线粒体膜电位（Δ Psim）下降，激活线粒体凋亡信号，诱导细胞死亡。p38丝裂原活化蛋白激酶（MAP）和细胞外信号调节激酶（ERK）介导SIN-1诱导的细胞凋亡。另一方面，一系列具有神经保护作用的炔丙胺衍生物，包括雷沙吉兰[N-炔丙基-1（R）氨基茚满]和（-）丙炔苯丙胺，通过稳定膜电位Δ Psi m，干预线粒体中活性氧-活性氮类物质对凋亡级联反应的激活。此外，雷沙吉兰诱导SH-SY 5 Y细胞中的抗凋亡Bcl-2和胶质细胞系源性神经营养因子（GDNF），这是通过ERK-核因子（NF）-κ B途径介导的。这些结果进行了讨论，在神经退行性疾病的神经元死亡和生存的调节氧化应激和线粒体的相互作用。
In mitochondria, oxidative phosphorylation and enzymatic oxidation of biogenic amines by monoamine oxidase produce reactive oxygen and nitrogen species, which are proposed to cause neuronal cell death in neurodegenerative disorders, including Parkinson's and Alzheimer's disease. In these disorders, mitochondrial dysfunction, increased oxidative stress, and accumulation of oxidation-modified proteins are involved in cell death in definite neurons. The interactions among these factors were studied by use of a peroxynitrite-generating agent, N-morpholino sydnonimine (SIN-1) and an inhibitor of complex 1, rotenone, in human dopaminergic SH-SY5Y cells. In control cells, peroxynitrite nitrated proteins, especially the subunits of mitochondrial complex I, as 3-nitrotyrosine, suggesting that neurons are exposed to constant oxidative stress even under physiological conditions. SIN-1 and an inhibitor of proteasome, carbobenzoxy-L-isoleucyl-gamma-t-butyl-L-alanyl-L-leucinal (PSI), increased markedly the levels of nitrated proteins with concomitant induction of apoptosis in the cells. Rotenone induced mitochondrial dysfunction and accumulation and aggregation of proteins modified with acrolein, an aldehyde product of lipid peroxidation in the cells. At the same time, the activity of the 20S beta-subunit of proteasome was reduced significantly, which degrades oxidative-modified protein. The mechanism was proved to be the result of the modification of the 20S beta-subunit with acrolein and to the binding of other acrolein-modified proteins to the 20S beta-subunit.Increased oxidative stress caused by SIN-1 treatment induced a decline in the mitochondrial membrane potential, Delta Psi m, and activated mitochondrial apoptotic signaling and induced cell death in SH-SY5Y cells. As another pathway, p38 mitogen-activated protein (MAP) kinase and exracellular signal-regulated kinase (ERK) mediated apoptosis induced by SIN-1. On the other hand, a series of neuroprotective propargylamine derivatives, including rasagiline [N-propargyl-1(R)aminoindan] and (-)deprenyl, intervened in the activation of apoptotic cascade by reactive oxygen species-reactive nitrogen species in mitochondria through stabilization of the membrane potential, Delta Psi m. In addition, rasagiline induced antiapoptotic Bcl-2 and glial cell line-derived neurotrophic factor (GDNF) in SH-SY5Y cells, which was mediated by the ERK-nuclear factor (NF)-kappa B pathway. These results are discussed in relation to the interaction of oxidative stress and mitochondria in the regulation of neuronal death and survival in neurodegenerative diseases.