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Mol Cell. 2019 Jan 17;73(2):354-363.e3. doi: 10.1016/j.molcel.2018.10.042. Epub 2018 Dec 20.

Role of Mitochondria in Ferroptosis.

Author information

1
The HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China; Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA. Electronic address: gaominghui@hit.edu.cn.
2
Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA.
3
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA.
4
Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA; BCMB Allied Program, Weill Cornell Graduate School of Medical Sciences, New York City, NY 10065, USA.
5
Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA. Electronic address: jiangx@mskcc.org.

Abstract

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.

PMID:
30581146
PMCID:
PMC6338496
[Available on 2020-01-17]
DOI:
10.1016/j.molcel.2018.10.042
[Indexed for MEDLINE]

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