Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7

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 mitochon...

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Published in:Nature cell biology Vol. 25; no. 2; pp. 246 - 257
Main Authors: Deshwal, Soni, Onishi, Mashun, Tatsuta, Takashi, Bartsch, Tim, Cors, Eileen, Ried, Katharina, Lemke, Kathrin, Nolte, Hendrik, Giavalisco, Patrick, Langer, Thomas
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.02.2023
Nature Publishing Group
Subjects:
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Biological Transport
Biomedical and Life Sciences
Cancer Research
Carrier Proteins - metabolism
Cell Biology
Coenzyme Q
Cristae
Cytosol
Developmental Biology
Electron Transport
Ferroptosis
Intracellular
Lecithin
Life Sciences
Lipid peroxidation
Lipids
Localization
Membranes
Mitochondria
Mitochondria - metabolism
Mitochondrial Membranes - metabolism
Morphogenesis
Oxidation-Reduction
Oxidative phosphorylation
Peroxidation
Phosphatidylcholine
Phosphorylation
Protease
Proteins
Stem Cells
Synthesis
Ubiquinone - metabolism
Ubiquinone - pharmacology
Vitamin C
ISSN:1465-7392, 1476-4679, 1476-4679
Online Access:Get full text
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Summary: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. Deshwal et al. show that the protease PARL regulates coenzyme Q (CoQ) via the lipid transfer protein STARD7. Mitochondrial STARD7 ensures CoQ synthesis; cytosolic STARD7 preserves CoQ transport to the membrane, protecting cells against ferroptosis.
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ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/s41556-022-01071-y