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线粒体通过 STARD7 调节细胞内辅酶 Q 转运和铁死亡抵抗。

Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.

机构信息

Max Planck Institute for Biology of Ageing, Cologne, Germany.

Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

出版信息

Nat Cell Biol. 2023 Feb;25(2):246-257. doi: 10.1038/s41556-022-01071-y. Epub 2023 Jan 19.

DOI:10.1038/s41556-022-01071-y
PMID:36658222
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9928583/
Abstract

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.

摘要

辅酶 Q（或泛醌）是一种氧化还原活性脂质，作为线粒体呼吸链中的通用电子载体和质膜中的抗氧化剂，限制脂质过氧化和铁死亡。细胞内辅酶 Q 合成后在细胞内分布的机制尚不清楚。在这里，我们确定胞质脂质转移蛋白 STARD7 是细胞内辅酶 Q 转运的关键因素和铁死亡的抑制剂。STARD7 被菱形蛋白酶 PARL 切割后定位于线粒体的膜间隙和胞质中，从而确保了辅酶 Q 在线粒体中的合成及其向质膜的转运。虽然线粒体 STARD7 可以维持辅酶 Q 的合成、氧化磷酸化功能和嵴形态发生，但胞质 STARD7 对于辅酶 Q 向质膜的转运和防止铁死亡是必需的。辅酶 Q 变体在体外与磷脂酰胆碱竞争与纯化的 STARD7 结合。胞质 STARD7 的过表达增加了细胞的铁死亡抗性，但限制了线粒体中辅酶 Q 的丰度和呼吸细胞的生长。因此，我们的研究结果表明需要通过 PARL 介导的 STARD7 加工来协调辅酶 Q 的合成和细胞分布，并确定 PARL 和 STARD7 是干扰铁死亡的有前途的靶点。

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