Muscle mitohormesis promotes longevity via systemic repression of insulin signaling.
Muscle mitohormesis promotes longevity via systemic repression of insulin signaling.
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DOI：
10.1016/j.cell.2013.09.021
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发表时间：
2013-10-24
期刊：
影响因子：
64.5
通讯作者：
Perrimon N
中科院分区：
文献类型：
--
作者：
Owusu-Ansah E;Song W;Perrimon N
线粒体功能障碍通常与衰老有关。为了系统地表征肌肉线粒体扰动引发的代偿性应激信号级联反应，我们分析了果蝇肌肉线粒体损伤模型。我们发现，轻度的肌肉线粒体损伤可以保护线粒体功能，阻止肌肉功能和结构的年龄依赖性恶化，延长寿命。引人注目的是，这种效应是由至少两个促长寿补偿信号模块介导的：一个涉及肌肉限制性氧化还原依赖性诱导基因，调节线粒体未折叠蛋白反应（UPRmt）;另一个涉及转录诱导果蝇直系同源的胰岛素样生长因子结合蛋白7，它全身拮抗胰岛素信号，并促进线粒体自噬。鉴于哺乳动物中存在几种分泌的IGF结合蛋白（IGFBPs），我们的工作提出了人类肌肉线粒体损伤可能类似地导致IGFBPs分泌的可能性，对与异常胰岛素信号相关的疾病具有重要影响。
Mitochondrial dysfunction is usually associated with aging. To systematically characterize the compensatory stress signaling cascades triggered in response to muscle mitochondrial perturbation, we analyzed a Drosophila model of muscle mitochondrial injury. We find that mild muscle mitochondrial distress preserves mitochondrial function, impedes the age-dependent deterioration of muscle function and architecture, and prolongs lifespan. Strikingly, this effect is mediated by at least two pro-longevity compensatory signaling modules: one involving a muscle-restricted redox-dependent induction of genes that regulate the mitochondrial unfolded protein response (UPRmt); and another involving the transcriptional induction of the Drosophila ortholog of insulin-like growth factor binding protein 7, which systemically antagonizes insulin signaling, and facilitates mitophagy. Given that several secreted IGF-binding proteins (IGFBPs) exist in mammals, our work raises the possibility that muscle mitochondrial injury in humans may similarly result in the secretion of IGFBPs, with important ramifications for diseases associated with aberrant insulin signaling.
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