The Ubiquitin Ligase Mul1 Induces Mitophagy in Skeletal Muscle in Response to Muscle-Wasting Stimuli (Retracted article. See vol. 22, pg. 1090, 2015)
The Ubiquitin Ligase Mul1 Induces Mitophagy in Skeletal Muscle in Response to Muscle-Wasting Stimuli (Retracted article. See vol. 22, pg. 1090, 2015)
复制标题
DOI：
10.1016/j.cmet.2012.10.005
复制
发表时间：
2012-11-07
期刊：
影响因子：
29
通讯作者：
Kambadur, Ravi
中科院分区：
文献类型：
--
作者：
Lokireddy, Sudarsanareddy;Wijesoma, Isuru W.;Kambadur, Ravi
最近的研究表明，功能障碍和随后的线粒体（线粒体自噬）的损失是骨骼肌萎缩的一个强有力的诱导剂。然而，在肌肉萎缩过程中线粒体功能失调的分子机制尚不清楚。在这份报告中，我们表明，不同的肌肉萎缩刺激上调线粒体E3泛素蛋白连接酶1（Mul 1），通过涉及FoxO 1/3转录因子的机制。Mul 1在骨骼肌和成肌细胞培养物中的过表达足以诱导线粒体自噬。一致的是，Mul 1抑制不仅防止了线粒体自噬，而且部分挽救了在肌肉萎缩刺激下观察到的肌肉萎缩。此外，Mul 1的上调在增加线粒体分裂的同时，导致线粒体融合蛋白Mfn 2的遍在化和降解。总的来说，这些数据解释了肌肉萎缩期间线粒体数量损失的分子基础。
Recent research reveals that dysfunction and subsequent loss of mitochondria (mitophagy) is a potent inducer of skeletal muscle wasting. However, the molecular mechanisms that govern the deregulation of mitochondrial function during muscle wasting are unclear. In this report, we show that different muscle-wasting stimuli upregulated mitochondrial E3 ubiquitin protein ligase 1 (Mul1), through a mechanism involving FoxO1/3 transcription factors. Overexpression of Mul1 in skeletal muscles and myoblast cultures was sufficient for the induction of mitophagy. Consistently, Mul1 suppression not only protected against mitophagy but also partially rescued the muscle wasting observed in response to muscle-wasting stimuli. In addition, upregulation of Mul1, while increasing mitochondrial fission, resulted in ubiquitination and degradation of the mitochondrial fusion protein Mfn2. Collectively, these data explain the molecular basis for the loss of mitochondrial number during muscle wasting.