Journal Article

Delivery of low-density lipoprotein from endocytic carriers to mitochondria supports steroidogenesis

Song, Bao-Liang, Luo, Jie, Sun, Pu-Yu, Wei, Jian, Zhou, Yu-Xia, Hu, Ao, Deng, Gang, Zhao, Xiaolu

2023

Overview

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. Zhou et al. describe an intracellular transport pathway of low-density lipoprotein (LDL)–LDL receptor from the plasma membrane that bypasses lysosomes and delivers cholesterol to mitochondria for steroidogenesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/109 / 13/51 / 13/89 / 14/19 / 14/28 / 14/35 / 38/22 / 38/23 / 38/47 / 38/77 / 38/90 / 631/45/287 / 631/80/313 / 82/80 / Biomedical and Life Sciences / Biosynthesis / Cancer Research / Cardiolipin / Cell Biology / Cholesterol / Cholesterol - metabolism / Cholesterol, LDL / Density / Developmental Biology / Endocytosis / Genetic screening / Genomes / Hormones / Intracellular / LDLR protein / Life Sciences / Lipids / Low density lipoprotein / Low density lipoprotein receptors / Lysosomes / Membrane fusion / Membrane proteins / Membrane Proteins - metabolism / Membrane vesicles / Membranes / Mitochondria / Mitochondria - metabolism / Phosphatidic acid / Proteins / Receptor density / Receptors / Stem Cells / Steroidogenesis / Steroids / Vesicle fusion / Vesicles