학술논문
Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria
Document Type
article
Author
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; Hevener, Andrea L
Source
Science Advances. 10(14)
Subject
Language
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.