Role of Mitochondria in Ferroptosis
Open accessAbstract
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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Ferroptosis induced by sustained cystine deprivation or erastin treatment perturbs cell proliferation beyond induction of lipid peroxidation.
“This is because ferroptosis induced by sustained cystine deprivation or erastin treatment perturbs cell proliferation beyond the induction lipid peroxidation (22).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [22]
The Results sections on mitochondrial regulation and membrane potential report that cystine deprivation or erastin induces lipid ROS and ferroptosis, and that proliferation can recover after erastin and the protective treatment CCCP are removed (page not available in our copy). They do not establish that sustained deprivation or erastin perturbs proliferation independently of, or beyond, lipid peroxidation. (LLM, conf=0.84)
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- Authors
- Gao, M., Yi, J., Zhu, J., Minikes, A. M., Monian, P., Thompson, C. B., & Jiang, X.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Gao, Minghui
- Jiang, Xuejun
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 73
- Issue
- 2
- Pages
- 354-363.e3
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6338496
- OpenAlex
- W2906319220
- Cited by
- 2,120
- References
- 11
- Citations by year
- 2026: 282 · 2025: 397 · 2024: 427 · 2023: 358 · 2022: 299 · 2021: 199 · 2020: 105 · 2019: 44 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 1
- FWCI
- 66.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01CA204232, R01CA201318)
- Geoffrey Beene Cancer Research
- National Natural Science Foundation of China (31871388)
- Leukemia and Lymphoma Society Fellowship
- NIH T32 fellowship (5T32GM008539-23)
- NCI cancer center (P30CA008748)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- ferroptosis, mitochondria, cysteine deprivation, GPX4, lipid peroxidation, TCA cycle, electron transport chain, glutaminolysis, fumarate hydratase, tumor suppression, regulated necrosis
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Citric Acid Cycle, Electron Transport, Enzyme Inhibitors, Fibroblasts, Fumarate Hydratase, Glutamine, Glutathione Peroxidase, Humans, Iron, Mitochondria, Mutation, Necrosis, Lipid Peroxidation, Signal Transduction, Reactive Oxygen Species, Electron Transport Chain Complex Proteins, Cell Line, Tumor, Mice, Membrane Potential, Mitochondrial
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