Drp1 controls Complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria

The Dynamin-related GTPase, 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. Herein, we show
that among human tissues, the highest number of gene correlations with
DNM1L  are 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.