Rab8a as a mitochondrial receptor for lipid droplets in skeletal muscle
Rab8a as a mitochondrial receptor for lipid droplets in skeletal muscle
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Rab8a 作为骨骼肌中脂滴的线粒体受体
DOI：
10.1016/j.devcel.2023.01.007
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发表时间：
2023-02-27
影响因子：
11.8
通讯作者：
Chen, Shuai
中科院分区：
文献类型：
--
作者：
Ouyang, Qian;Chen, Qiaoli;Chen, Shuai
脂质滴（LDs）和线粒体之间的动态相互作用控制着长链脂肪酸（LCFAs）从脂质滴中动员出来，以便在能量应激时于骨骼肌中进行线粒体β -氧化。然而，对于介导脂质滴 - 线粒体相互作用的连接复合物的组成和调控却知之甚少。在此，我们确定Rab8a是脂质滴在线粒体上的受体，它在骨骼肌中与脂质滴相关的PLIN5形成连接复合物。在大鼠L6骨骼肌细胞中，能量传感器AMPK会增加与GTP结合的活性Rab8a，在饥饿时通过与PLIN5结合促进脂质滴 - 线粒体相互作用。Rab8a - PLIN5连接复合物的组装还招募了脂肪甘油三酯脂酶（ATGL），它将长链脂肪酸从脂质滴中动员出来并转运到线粒体中进行β -氧化。在小鼠模型中，Rab8a缺乏会损害脂肪酸利用并降低运动耐力。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潜在调控机制。
Dynamic interaction between lipid droplets (LDs) and mitochondria controls the mobilization of long-chain fatty acids (LCFAs) from LDs for mitochondrial 0-oxidation in skeletal muscle in response to energy stress. However, little is known about the composition and regulation of the tethering complex mediating LD-mito-chondrion 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 0-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.