State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing 210061, China; Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing 210061, China.
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing 210061, China.
Dev Cell. 2023 Feb 27;58(4):289-305.e6. doi: 10.1016/j.devcel.2023.01.007. Epub 2023 Feb 16.
Dynamic interaction between lipid droplets (LDs) and mitochondria controls the mobilization of long-chain fatty acids (LCFAs) from LDs for mitochondrial β-oxidation in skeletal muscle in response to energy stress. However, little is known about the composition and regulation of the tethering complex mediating LD-mitochondrion interaction. Here, we identify Rab8a as a mitochondrial receptor for LDs forming the tethering complex with the LD-associated PLIN5 in skeletal muscle. In rat L6 skeletal muscle cells, the energy sensor AMPK increases the GTP-bound active Rab8a that promotes LD-mitochondrion interaction through binding to PLIN5 upon starvation. The assembly of the Rab8a-PLIN5 tethering complex also recruits the adipose triglyceride lipase (ATGL), which couples LCFA mobilization from LDs with its transfer into mitochondria for β-oxidation. Rab8a deficiency impairs fatty acid utilization and decreases endurance during exercise in a mouse model. These findings may help to elucidate the regulatory mechanisms underlying the beneficial effects of exercise on lipid homeostasis control.
脂滴 (LDs) 和线粒体之间的动态相互作用控制着长链脂肪酸 (LCFAs) 从 LDs 向线粒体 β-氧化的动员，以响应能量应激。然而，关于介导 LD-线粒体相互作用的连接复合物的组成和调节知之甚少。在这里，我们确定 Rab8a 是一种与 LD 相关的 PLIN5 形成连接复合物的线粒体受体，存在于骨骼肌中。在大鼠 L6 骨骼肌细胞中，能量传感器 AMPK 增加了结合有 GDP 的活性 Rab8a，在饥饿时通过与 PLIN5 结合促进 LD-线粒体的相互作用。Rab8a-PLIN5 连接复合物的组装还招募了脂肪甘油三酯脂肪酶 (ATGL)，它将 LCFA 从 LDs 中动员并将其转移到线粒体中进行 β-氧化。Rab8a 缺乏会损害脂肪酸的利用，并降低运动小鼠模型中的耐力。这些发现可能有助于阐明运动对脂质动态平衡控制的有益影响的调节机制。
