Role of Mitochondria in Ferroptosis

Ferroptosis is a regulated necrosis process driven by iron-dependent lipid peroxidation. Although ferroptosis and cellular metabolism interplay with one another, whether mitochondria are involved in ferroptosis is under debate. Here, we demonstrate that mitochondria play a crucial role in cysteine-d...

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Published in:Molecular cell Vol. 73; no. 2; p. 354
Main Authors: Gao, Minghui, Yi, Junmei, Zhu, Jiajun, Minikes, Alexander M, Monian, Prashant, Thompson, Craig B, Jiang, Xuejun
Format: Journal Article
Language:English
Published: United States 17.01.2019
Subjects:
Animals
Cell Line, Tumor
Citric Acid Cycle - drug effects
Electron Transport
Electron Transport Chain Complex Proteins - antagonists & inhibitors
Electron Transport Chain Complex Proteins - metabolism
Enzyme Inhibitors - pharmacology
Fibroblasts - drug effects
Fibroblasts - enzymology
Fibroblasts - pathology
Fumarate Hydratase - genetics
Fumarate Hydratase - metabolism
Glutamine - metabolism
Glutathione Peroxidase - genetics
Glutathione Peroxidase - metabolism
Humans
Iron - metabolism
Lipid Peroxidation - drug effects
Membrane Potential, Mitochondrial
Mice
Mitochondria - drug effects
Mitochondria - enzymology
Mitochondria - genetics
Mitochondria - pathology
Mutation
Necrosis
Phospholipid Hydroperoxide Glutathione Peroxidase
Reactive Oxygen Species - metabolism
Signal Transduction
ISSN:1097-4164, 1097-4164
Online Access:Get more information
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Summary:Ferroptosis is a regulated necrosis process driven by iron-dependent lipid peroxidation. Although ferroptosis and cellular metabolism interplay with one another, whether mitochondria are involved in ferroptosis is under debate. Here, we demonstrate that mitochondria play a crucial role in cysteine-deprivation-induced ferroptosis but not in that induced by inhibiting glutathione peroxidase-4 (GPX4), the most downstream component of the ferroptosis pathway. Mechanistically, cysteine deprivation leads to mitochondrial membrane potential hyperpolarization and lipid peroxide accumulation. Inhibition of mitochondrial TCA cycle or electron transfer chain (ETC) mitigated mitochondrial membrane potential hyperpolarization, lipid peroxide accumulation, and ferroptosis. Blockage of glutaminolysis had the same inhibitory effect, which was counteracted by supplying downstream TCA cycle intermediates. Importantly, loss of function of fumarate hydratase, a tumor suppressor and TCA cycle component, confers resistance to cysteine-deprivation-induced ferroptosis. Collectively, this work demonstrates the crucial role of mitochondria in cysteine-deprivation-induced ferroptosis and implicates ferroptosis in tumor suppression.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2018.10.042