Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice
Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice
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DOI：
10.1523/jneurosci.3829-04.2005
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发表时间：
2005-01-05
影响因子：
5.3
通讯作者：
Moraes, CT
中科院分区：
文献类型：
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作者：
Kirkinezos, IG;Bacman, SR;Moraes, CT
突变型铜锌超氧化物歧化酶 1 (SOD1) 的“功能获得”毒性与一些肌萎缩侧索硬化症 (ALS) 家族病例的发病机制有关。人类 SOD1 基因突变体在小鼠体内的表达会导致运动神经元退化，导致进行性肌肉无力和后肢瘫痪。过度表达突变型人类 SOD1 基因 (G93A-SOD1) 的转基因小鼠被用来检查家族性 ALS 中线粒体的参与情况。我们观察到 G93A-SOD1 小鼠大脑和脊髓的线粒体呼吸减少。这种减少仅在呼吸链的最后一步（复合体 IV）显着，并且在转基因野生型 SOD1 和非转基因小鼠中未观察到。有趣的是，这种下降甚至在小鼠很小的时候就很明显，远在任何临床症状出现之前。这种效应似乎是中枢神经系统特异性的，因为没有观察到肝线粒体减少。当使用还原型细胞色素c作为电子供体时，G93A-SOD1和对照小鼠脑线粒体之间复杂的IV呼吸的差异被消除，从而精确定位了细胞色素c的缺陷。线粒体研究表明，G93A-SOD1 小鼠大脑中的细胞色素 c 与线粒体内膜 (IMM) 的关联减少。 G93A-SOD1 小鼠脑线粒体脂质（包括心磷脂）的过氧化作用增加。这些结果表明突变体 SOD1 可以破坏细胞色素 c 与 IMM 的结合，从而启动细胞凋亡程序。
A "gain-of-function" toxic property of mutant Cu-Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of the human SOD1 gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS. We observed a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochrome c was used as an electron donor, pinpointing the defect to cytochrome c. Submitochondrial studies showed that cytochrome c in the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program.