School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Cell Metab. 2012 Nov 7;16(5):613-24. doi: 10.1016/j.cmet.2012.10.005.
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.
最近的研究表明，线粒体功能障碍和随后的损失（自噬）是骨骼肌消耗的有力诱导因素。然而，调控肌肉消耗过程中线粒体功能失调的分子机制尚不清楚。在本报告中，我们表明，不同的肌肉消耗刺激物通过涉及 FoxO1/3 转录因子的机制上调了线粒体 E3 泛素蛋白连接酶 1（Mul1）。Mul1 在骨骼肌和肌母细胞培养物中的过表达足以诱导自噬。一致地，Mul1 的抑制不仅防止了自噬，而且部分挽救了对肌肉消耗刺激的观察到的肌肉消耗。此外，Mul1 的上调虽然增加了线粒体分裂，但导致线粒体融合蛋白 Mfn2 的泛素化和降解。总之，这些数据解释了肌肉消耗过程中线粒体数量减少的分子基础。
