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A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Jun 28; Vol. 119 (26), pp. e2121987119. Date of Electronic Publication: 2022 Jun 24. - Publication Year :
- 2022
-
Abstract
- Mechanisms of defense against ferroptosis (an iron-dependent form of cell death induced by lipid peroxidation) in cellular organelles remain poorly understood, hindering our ability to target ferroptosis in disease treatment. In this study, metabolomic analyses revealed that treatment of cancer cells with glutathione peroxidase 4 (GPX4) inhibitors results in intracellular glycerol-3-phosphate (G3P) depletion. We further showed that supplementation of cancer cells with G3P attenuates ferroptosis induced by GPX4 inhibitors in a G3P dehydrogenase 2 (GPD2)-dependent manner; GPD2 deletion sensitizes cancer cells to GPX4 inhibition-induced mitochondrial lipid peroxidation and ferroptosis, and combined deletion of GPX4 and GPD2 synergistically suppresses tumor growth by inducing ferroptosis in vivo. Mechanistically, inner mitochondrial membrane-localized GPD2 couples G3P oxidation with ubiquinone reduction to ubiquinol, which acts as a radical-trapping antioxidant to suppress ferroptosis in mitochondria. Taken together, these results reveal that GPD2 participates in ferroptosis defense in mitochondria by generating ubiquinol.
- Subjects :
- Cell Line, Tumor
Humans
Phospholipid Hydroperoxide Glutathione Peroxidase metabolism
Ferroptosis genetics
Glycerolphosphate Dehydrogenase antagonists & inhibitors
Glycerolphosphate Dehydrogenase genetics
Glycerolphosphate Dehydrogenase metabolism
Lipid Peroxidation genetics
Mitochondria enzymology
Mitochondrial Proteins genetics
Mitochondrial Proteins metabolism
Neoplasms enzymology
Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 119
- Issue :
- 26
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 35749365
- Full Text :
- https://doi.org/10.1073/pnas.2121987119