31-OR: Skeletal Muscle Drp1 Maintains Metabolic Homeostasis through Preserving Mitochondrial Complex II Function

Dynamin-related protein 1 (Drp1) is a primary mediator of mitochondrial fission, the process of dividing an individual mitochondrion into two organelles. We have previously shown that Drp1 expression is reduced in muscle of dysglycemic men compared to healthy normoglycemic men at rest and during exercise. Moreover, our laboratory has observed mitochondrial fission incompetence in several mouse models of skeletal muscle insulin resistance. To determine whether mitochondrial fission incompetence alters muscle metabolism and insulin action, we generated two mouse models with muscle-selective conventional and inducible deletion alleles of Drp1 (mDrp1KO and miDrp1KO respectively). Muscle deletion of Drp1 reduced fatty acid oxidation, promoted the accumulation of myocellular lipids, elevated the respiratory exchange ratio (RER) assessed by indirect calorimetry, and impaired insulin action. Examination of mitochondria from mDrp1KOmuscle using transmission electron microscopy revealed a notably elongated morphology compared to Controlf/f. Moreover, real time respirometry revealed an impairment in mitochondrial complex II activity that was a likely consequence of defective SDH assembly. Complex II assembly factor SDHAF2, required for flavination of the SDHA subunit and complex II activity, was markedly reduced in both Drp1 deletion mouse models and in Drp1 knockdown (KD) myotubes. Using immunoprecipitation approaches in mouse muscle and murine myotubes, we determined that SDHAF2 associates with Drp1, and that this relationship is critical for the translocation of SDHAF2 protein into mitochondria during fission. Pharmacological inhibition of complex II recapitulated the impairment in lipid oxidation and insulin action seen in mDrp1KO and Drp1KD cells. Our findings indicate that Drp1 is critical for fatty acid oxidation and the maintenance of insulin action by controlling the assembly and function of mitochondrial complex II. Disclosure Z. Zhou: None. A.L. Hevener: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK109724)