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Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
Nat. Cell Biol. 25, 246-257 (2023)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Language
english
Publication Year
2023
HGF-reported in Year
2023
ISSN (print) / ISBN
1465-7392
e-ISSN
1476-4679
Journal
Nature Cell Biology
Quellenangaben
Volume: 25,
Issue: 2,
Pages: 246-257
Publisher
Nature Publishing Group
Reviewing status
Peer reviewed
Institute(s)
Institute of Metabolism and Cell Death (MCD)
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-509900-024
PubMed ID
36658222
Erfassungsdatum
2025-02-26