Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Sci Adv. 2024 Apr 5;10(14):eadl0389. doi: 10.1126/sciadv.adl0389. Epub 2024 Apr 3.
The dynamin-related guanosine triphosphatase, Drp1 (encoded by ), 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 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.
与 GTP 酶相关的动力蛋白 Drp1（由 编码）在线粒体分裂中发挥核心作用，是许多细胞过程所必需的；然而，其在肌肉代谢中的作用仍不清楚。在这里，我们发现，在人体组织中，与 相关性最高的基因是骨骼肌。在雄性小鼠的肌肉中，Drp1（Drp1-KD）的敲低促进了线粒体的过度融合。在 Drp1-KD 肌肉中观察到脂肪酸氧化减少和胰岛素作用受损，同时肌肉琥珀酸增加。肌肉 Drp1-KD 减少了由于琥珀酸脱氢酶组装因子 2（Sdhaf2）的线粒体易位减少而导致的复合物 II 的组装和活性。恢复 Sdhaf2 使 Drp1-KD 肌细胞中的复合物 II 活性、脂质氧化和胰岛素作用正常化。Drp1 对于维持线粒体复合物 II 的组装、脂质氧化和胰岛素敏感性至关重要，这表明线粒体形态和骨骼肌代谢之间存在机制联系，这在对抗与代谢相关的疾病方面具有临床意义。
