RETRACTED: The Ubiquitin Ligase Mul1 Induces Mitophagy in Skeletal Muscle in Response to Muscle-Wasting Stimuli

• DOI: 10.1016/j.cmet.2012.10.005
• Publication Date: 2012-11-06T16:04:33Z
• Authors: Sudarsanareddy Lo...; Isuru W. Wijesoma; Serena Teng; Sabeera Bonala; Peter D. Gluckman; Craig McFarlane; Mridula Sharma; Ravi Kambadur
• Keywords: 0301 basic medicine; Physiology; Ubiquitin-Protein Ligases; DNA, Mitochondrial; Dexamethasone; Cell Line; GTP Phosphohydrolases; Mitochondrial Proteins; Myoblasts; Mice; 03 medical and health sciences; Animals; Molecular Biology; Glucocorticoids; Membrane Potential, Mitochondrial; Mitophagy; Ubiquitination; Forkhead Transcription Factors; Cell Biology; Myostatin; :Science::Biological sciences [DRNTU]; Mitochondria; Up-Regulation; Muscular Atrophy; Signal Transduction

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.