The role of PGC-1α on mitochondrial function and apoptotic susceptibility in muscle
The role of PGC-1α on mitochondrial function and apoptotic susceptibility in muscle
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DOI：
10.1152/ajpcell.00070.2009
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发表时间：
2009-07-01
影响因子：
5.5
通讯作者：
Hood, David A.
中科院分区：
文献类型：
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作者：
Adhihetty, Peter J.;Uguccioni, Giulia;Hood, David A.
Adhihetty PJ，Uguccioni G，Leick L，Hidalgo J，Pilegaard H，Hood DA. The role of PGC-1 alpha on mitochondrial function and apoptosis susceptibility in muscle.美国生理学杂志细胞生理学297：C217-C225，2009年。首次发表于2009年5月13日; doi：10.1152/ajpcell.00070.2009。线粒体对于细胞生物能量学是至关重要的，并且它们介导细胞内的凋亡。我们使用全身过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1 α）敲除（KO）动物来研究其对肌肉和其他组织（脑、肝和胰腺）中细胞器功能、凋亡信号传导和细胞色素c氧化酶活性（线粒体含量的指标）的作用。PGC-1 α的缺乏降低了所有肌肉中的线粒体含量（17-44%; P < 0.05），但对脑、肝和胰腺没有影响。然而，参与线粒体DNA维持[转录因子A（Tfam）]、输入（Tim 23）和重塑[线粒体融合蛋白2（Mfn 2）和动力蛋白相关蛋白1（Drp 1）]的蛋白质的组织表达与PGC-1 alpha KO动物中线粒体含量的降低并不平行。这些蛋白质在高氧化心脏中保持不变或上调（P < 0.05），表明线粒体组成的变化。肌细胞器组成的变化也明显从肌膜下和肌原纤维间线粒体呼吸的改变，这是在PGC-1 α的情况下受损。然而，经抗氧化训练的KO动物并未表现出线粒体呼吸减少。线粒体活性氧（ROS）的产生不受PGC-1 α缺乏的影响，但在外源性ROS处理后，来自PGC-1 α KO动物的肌膜下线粒体释放的细胞色素c量比WT动物更大量。我们的研究结果表明，PGC-1 α的缺乏导致1）依赖于基础氧化能力的线粒体含量的肌肉类型特异性抑制，2）线粒体组成的改变，3）线粒体呼吸功能受损，可以通过训练来改善，以及4）从肌膜下线粒体释放更多的基础蛋白，表明线粒体凋亡易感性增强。
Adhihetty PJ, Uguccioni G, Leick L, Hidalgo J, Pilegaard H, Hood DA. The role of PGC-1 alpha on mitochondrial function and apoptotic susceptibility in muscle. Am J Physiol Cell Physiol 297: C217-C225, 2009. First published May 13, 2009; doi:10.1152/ajpcell.00070.2009.-Mitochondria are critical for cellular bioenergetics, and they mediate apoptosis within cells. We used whole body peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) knockout (KO) animals to investigate its role on organelle function, apoptotic signaling, and cytochrome-c oxidase activity, an indicator of mitochondrial content, in muscle and other tissues (brain, liver, and pancreas). Lack of PGC-1 alpha reduced mitochondrial content in all muscles (17-44%; P < 0.05) but had no effect in brain, liver, and pancreas. However, the tissue expression of proteins involved in mitochondrial DNA maintenance [transcription factor A (Tfam)], import (Tim23), and remodeling [mitofusin 2 (Mfn2) and dynamin-related protein 1 (Drp1)] did not parallel the decrease in mitochondrial content in PGC-1 alpha KO animals. These proteins remained unchanged or were upregulated (P < 0.05) in the highly oxidative heart, indicating a change in mitochondrial composition. A change in muscle organelle composition was also evident from the alterations in subsarcolemmal and intermyofibrillar mitochondrial respiration, which was impaired in the absence of PGC-1 alpha. However, endurance-trained KO animals did not exhibit reduced mitochondrial respiration. Mitochondrial reactive oxygen species (ROS) production was not affected by the lack of PGC-1 alpha, but subsarcolemmal mitochondria from PGC-1 alpha KO animals released a greater amount of cytochrome c than in WT animals following exogenous ROS treatment. Our results indicate that the lack of PGC-1 alpha results in 1) a muscle type-specific suppression of mitochondrial content that depends on basal oxidative capacity, 2) an alteration in mitochondrial composition, 3) impaired mitochondrial respiratory function that can be improved by training, and 4) a greater basal protein release from subsarcolemmal mitochondria, indicating an enhanced mitochondrial apoptotic susceptibility.