德国马克斯普朗克衰老生物学研究所Thomas Langer课题组发现，线粒体通过STARD7调节细胞内辅酶Q转运和铁死亡抗性。2023年1月19日出版的《自然—细胞生物学》发表了这项成果。

他们鉴定了胞浆脂质转移蛋白STARD7作为细胞内辅酶Q转运的关键因子和铁死亡的抑制剂。在被菱形蛋白酶PARL切割时，STARD7在线粒体膜间空间和胞浆中的双重定位确保了辅酶Q在线粒体中的合成及其向质膜的转运。虽然线粒体STARD7保持辅酶Q合成、氧化磷酸化功能和嵴形态发生，但胞浆STARD7是辅酶Q运输至质膜所必需的，并可防止铁死亡。辅酶Q变体在体外与磷脂酰胆碱竞争与纯化的STARD7结合。胞浆STARD7的过度表达增加了细胞的铁死亡抵抗力，但限制了线粒体中辅酶Q的丰度和呼吸细胞的生长。因此，他们的研究结果表明，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，并将PARL和STARD7确定为干扰铁死亡的潜在靶点。

据悉，辅酶Q（或泛醌）是一种氧化还原活性脂质，在线粒体呼吸链中充当通用电子载体，在质膜中充当抗氧化剂，限制脂质过氧化和铁死亡。线粒体内合成后细胞辅酶Q分布的机制尚不清楚。

附：英文原文

Title: Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7

Author: Deshwal, Soni, Onishi, Mashun, Tatsuta, Takashi, Bartsch, Tim, Cors, Eileen, Ried, Katharina, Lemke, Kathrin, Nolte, Hendrik, Giavalisco, Patrick, Langer, Thomas

Issue&Volume: 2023-01-19

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.

DOI: 10.1038/s41556-022-01071-y

Source: https://www.nature.com/articles/s41556-022-01071-y