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 (LD) 和线粒体之间的动态相互作用控制来自 LD 的长链脂肪酸 (LCFA) 的动员，以响应能量应激在骨骼肌中进行线粒体 β-氧化。然而，关于介导 LD-线粒体相互作用的束缚复合物的组成和调节知之甚少。在这里，我们将 Rab8a 鉴定为 LD 的线粒体受体，与骨骼肌中的 LD 相关 PLIN5 形成束缚复合物。在大鼠 L6 骨骼肌细胞中，能量传感器 AMPK 增加 GTP 结合活性 Rab8a，在饥饿时通过结合 PLIN5 促进 LD-线粒体相互作用。Rab8a-PLIN5 束缚复合物的组装还募集了脂肪甘油三酯脂肪酶 (ATGL)，它将来自 LDs 的 LCFA 动员与其转移到线粒体中进行 β-氧化相结合。在小鼠模型中，Rab8a 缺乏会损害脂肪酸的利用并降低运动期间的耐力。这些发现可能有助于阐明运动对脂质稳态控制产生有益影响的调节机制。