Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis
Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis
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DOI：
10.1096/fj.02-1182fje
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发表时间：
2003-09-01
期刊：
影响因子：
4.8
通讯作者：
Loeffler, JP
中科院分区：
文献类型：
--
作者：
Dupuis, L;di Scala, F;Loeffler, JP
肌萎缩侧索硬化症（ALS）是一种主要影响运动神经元的神经退行性疾病。越来越多的证据表明ALS中存在线粒体缺陷。这些缺陷背后的精确分子机制尚不清楚。我们研究了线粒体解偶联蛋白（UCPs）的表达，线粒体功能的关键调节因子，在ALS小鼠模型（SOD1 G86R转基因小鼠）和人类散发性ALS的肌肉活检组织中。令人惊讶的是，在SOD1 G86R小鼠中，UCP，特别是UCP3，在骨骼肌中上调，但在脊髓中不上调。与这种表达模式相一致，ATP水平在疾病发作前1个月在肌肉中选择性耗尽，但在神经组织中没有，并且分离的线粒体的呼吸控制率降低。在实验失神经肌肉中未观察到UCP3上调，表明肌肉UCP3表达的变化与ALS的生理病理过程相关。这进一步得到了我们在人ALS肌肉活检中观察到的UCP3水平增加的支持。我们认为骨骼肌中UCP3的上调有助于ALS的特征性线粒体损伤和疾病的发作。此外，由于骨骼肌是一个关键的代谢组织，我们的研究结果表明，ALS可能不仅仅是由神经元事件，但也从更广泛的代谢缺陷。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily motor neurons. Growing evidence suggests a mitochondrial defect in ALS. The precise molecular mechanisms underlying those defects are unknown. We studied the expression of mitochondrial uncoupling proteins (UCPs), key regulators of mitochondrial functions, in tissues from a mouse model of ALS (SOD1 G86R transgenic mice) and from muscular biopsies of human sporadic ALS. Surprisingly, in SOD1 G86R mice, UCPs, and particularly UCP3, were upregulated in skeletal muscle but not in spinal cord. Consistent with this pattern of expression, ATP levels were selectively depleted in muscle but not in neural tissues 1 month before disease onset and the respiratory control ratio of isolated mitochondria is decreased. UCP3 up-regulation was not observed in experimentally denervated muscles, suggesting that changes in muscular UCP3 expression are associated with the physiopathological processes of ALS. This is further supported by our observation of increased UCP3 levels in human ALS muscular biopsies. We propose that UCP3 up-regulation in skeletal muscle contributes to the characteristic mitochondrial damage of ALS and to the onset of the disease. Moreover, since skeletal muscle is a key metabolic tissue, our findings suggest that ALS may not solely arise from neuronal events but also from more generalized metabolic defects.