Mitochondrial dysfunction in S0D1G93A-bearing astrocytes promotes motor neuron degeneration:: Prevention by mitochondrial-targeted antioxidants
Mitochondrial dysfunction in S0D1G93A-bearing astrocytes promotes motor neuron degeneration:: Prevention by mitochondrial-targeted antioxidants
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DOI：
10.1523/jneurosci.5308-07.2008
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发表时间：
2008-04-16
影响因子：
5.3
通讯作者：
Radi, Rafael
中科院分区：
文献类型：
--
作者：
Cassina, Patricia;Cassina, Adriana;Radi, Rafael
线粒体功能障碍和氧化应激导致肌萎缩侧索硬化症（ALS）的运动神经元变性。最近的研究表明，星形胶质细胞表达超氧化物歧化酶-1（SOD 1）的突变可能有助于ALS运动神经元损伤。在这里，我们提供的证据表明，线粒体功能障碍S 0 D1（G93 A）大鼠星形胶质细胞导致星形胶质细胞诱导运动神经元凋亡。S 0 D1（G93 A）大鼠星形胶质细胞的线粒体显示出呼吸功能缺陷，包括耗氧量降低，缺乏ADP依赖性呼吸控制和膜电位降低。蛋白3-硝基酪氨酸免疫化学检测从S 0 D1（G93 A）星形胶质细胞的线粒体蛋白，这表明线粒体缺陷与氮氧化损伤。此外，在S 0 D1（G93 A）星形胶质细胞中，线粒体中超氧自由基的形成增加。在从S 0 D1（G93 A）大鼠的脊髓分离的线粒体中发现了类似的缺陷，并且用自旋捕获器5，5-二甲基-1-吡咯啉N-氧化物预处理动物恢复了线粒体功能，在体内与线粒体蛋白形成加合物。如前所述，与非转基因的相比，S 0 D1（G93 A）星形胶质细胞在共培养物中诱导运动神经元死亡。当用线粒体抑制剂处理非转基因星形胶质细胞时，这种行为被重演。值得注意的是，运动神经元的损失是防止预孵育的S 0 D1（G93 A）星形胶质细胞与抗氧化剂和一氧化氮合酶抑制剂。特别是，低浓度（类似于10 nM）的两种胆固醇靶向的抗氧化剂，泛醌和羧基-乙酰基氮氧化物，每个共价偶联到一个三苯基膦阳离子（Mito-Q和Mito-CP，分别），防止线粒体功能障碍，减少超氧化物的产生在S 0 D1（G93 A）星形胶质细胞，并恢复运动神经元存活。总之，我们的研究结果表明，星形胶质细胞中的线粒体功能障碍严重影响运动神经元的存活，并支持ALS治疗中神经靶向抗氧化剂的潜在药理学效用。
Mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Recent reports indicate that astrocytes expressing the mutations of superoxide dismutase- 1 (SOD1) may contribute to motor neuron injury in ALS. Here, we provide evidence that mitochondrial dysfunction in S0D1(G93A) rat astrocytes causes astrocytes to induce apoptosis of motor neurons. Mitochondria from S0D1(G93A) rat astrocytes displayed a defective respiratory function, including decreased oxygen consumption, lack of ADP-dependent respiratory control, and decreased membrane potential. Protein 3-nitrotyrosine was detected immunochemically in mitochondrial proteins from S0D1(G93A) astrocytes, suggesting that mitochondrial defects were associated with nitroxidative damage. Furthermore, superoxide radical formation in mitochondria was increased in S0D1(G93A) astrocytes. Similar defects were found in mitochondria isolated from the spinal cord of S0D1(G93A) rats, and pretreatment of animals with the spin trap 5,5-dimethyl-1-pyrroline N-oxide restored mitochondrial function, forming adducts with mitochondrial proteins in vivo. As shown previously, S0D1(G93A) astrocytes induced death of motor neurons in cocultures, compared with nontransgenic ones. This behavior was recapitulated when nontransgenic astrocytes were treated with mitochondrial inhibitors. Remarkably, motor neuron loss was prevented by preincubation of S0D1(G93A) astrocytes with antioxidants and nitric oxide synthase inhibitors. In particular, low concentrations (similar to 10 nM) of two mitochondrial-targeted antioxidants, ubiquinone and carboxy-proxyl nitroxide, each covalently coupled to a triphenylphosphonium cation (Mito-Q and Mito-CP, respectively), prevented mitochondrial dysfunction, reduced superoxide production in S0D1(G93A) astrocytes, and restored motor neuron survival. Together, our results indicate that mitochondrial dysfunction in astrocytes critically influences motor neuron survival and support the potential pharmacological utility of mitochondrial-targeted antioxidants in ALS treatment.