College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China.
Nat Cell Biol. 2023 Jul;25(7):937-949. doi: 10.1038/s41556-023-01160-6. Epub 2023 Jun 5.
The low-density lipoprotein (LDL) is a major cholesterol carrier in circulation and is internalized into cells through LDL receptor (LDLR)-mediated endocytosis. The LDLR protein is highly expressed in the steroidogenic organs and LDL cholesterol is an important source for steroidogenesis. Cholesterol must be transported into the mitochondria, where steroid hormone biosynthesis initiates. However, how LDL cholesterol is conveyed to the mitochondria is poorly defined. Here, through genome-wide small hairpin RNA screening, we find that the outer mitochondrial membrane protein phospholipase D6 (PLD6), which hydrolyses cardiolipin to phosphatidic acid, accelerates LDLR degradation. PLD6 promotes the entrance of LDL and LDLR into the mitochondria, where LDLR is degraded by mitochondrial proteases and LDL-carried cholesterol is used for steroid hormone biosynthesis. Mechanistically, the outer mitochondrial membrane protein CISD2 binds to the cytosolic tail of LDLR and tethers LDLR vesicles to the mitochondria. The fusogenic lipid phosphatidic acid generated by PLD6 facilitates the membrane fusion of LDLR vesicles with the mitochondria. This intracellular transport pathway of LDL-LDLR bypasses the lysosomes and delivers cholesterol to the mitochondria for steroidogenesis.
低密度脂蛋白（LDL）是循环中主要的胆固醇载体，通过 LDL 受体（LDLR）介导的内吞作用被内化到细胞中。LDLR 蛋白在甾体生成器官中高度表达，LDL 胆固醇是甾体生成的重要来源。胆固醇必须运输到线粒体，在那里开始合成甾体激素。然而，LDL 胆固醇如何被转运到线粒体还不清楚。在这里，我们通过全基因组短发夹 RNA 筛选，发现水解心磷脂为磷酸甘油的外线粒体膜蛋白磷脂酶 D6（PLD6）加速 LDLR 降解。PLD6 促进 LDL 和 LDLR 进入线粒体，在那里 LDLR 被线粒体蛋白酶降解，LDL 携带的胆固醇用于合成甾体激素。在机制上，外线粒体膜蛋白 CISD2 与 LDLR 的胞质尾部结合，并将 LDLR 囊泡锚定在线粒体上。PLD6 产生的融合脂质磷酸甘油促进 LDLR 囊泡与线粒体的膜融合。LDL-LDLR 的这种细胞内转运途径绕过溶酶体，将胆固醇输送到线粒体进行甾体生成。
