title: The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli.
abstract: 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.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Sudarsanareddy
authors.initials: S
authors.lastname: Lokireddy
authors.forename: Isuru W
authors.initials: IW
authors.lastname: Wijesoma
authors.forename: Serena
authors.initials: S
authors.lastname: Teng
authors.forename: Sabeera
authors.initials: S
authors.lastname: Bonala
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gluckman
authors.forename: Craig
authors.initials: C
authors.lastname: McFarlane
authors.forename: Mridula
authors.initials: M
authors.lastname: Sharma
authors.forename: Ravi
authors.initials: R
authors.lastname: Kambadur
mesh_terms: D000818:Animals; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects*; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism; D055435:Myostatin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D004272:DNA, Mitochondrial; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D024101:Mitochondrial Proteins; D055435:Myostatin; D003907:Dexamethasone; C000608240:MUL1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse