A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria.

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.

• Authors: Shiqi Wu, Chao Mao, Lavanya Kondiparthi, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 26 Pg. e2121987119 (06 28 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 35749365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Mitochondrial Proteins
• GPD2 protein, human
• Glycerolphosphate Dehydrogenase
• Phospholipid Hydroperoxide Glutathione Peroxidase

Topics

• Cell Line, Tumor
• Ferroptosis (genetics)
• Glycerolphosphate Dehydrogenase (antagonists & inhibitors, genetics, metabolism)
• Humans
• Lipid Peroxidation (genetics)
• Mitochondria (enzymology)
• Mitochondrial Proteins (genetics, metabolism)
• Neoplasms (enzymology, pathology)
• Phospholipid Hydroperoxide Glutathione Peroxidase (metabolism)