1. Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria
- Author
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Zhou, Zhenqi, Ma, Alice, Moore, Timothy M, Wolf, Dane M, Yang, Nicole, Tran, Peter, Segawa, Mayuko, Strumwasser, Alexander R, Ren, Wenjuan, Fu, Kai, Wanagat, Jonathan, van der Bliek, Alexander M, Crosbie-Watson, Rachelle, Liesa, Marc, Stiles, Linsey, Acin-Perez, Rebecca, Mahata, Sushil, Shirihai, Orian, Goodarzi, Mark O, Handzlik, Michal, Metallo, Christian M, Walker, David W, and Hevener, Andrea L
- Subjects
Biochemistry and Cell Biology ,Health Sciences ,Sports Science and Exercise ,Biological Sciences ,Metabolic and endocrine ,Musculoskeletal ,Male ,Humans ,Mice ,Animals ,Succinate Dehydrogenase ,Mitochondrial Proteins ,Mitochondria ,Muscle ,Skeletal ,Insulins ,Lipids - Abstract
The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.
- Published
- 2024