Role of mitochondria in ferroptosis Journal Article

Authors: Gao, M.; Yi, J.; Zhu, J.; Minikes, A. M.; Monian, P.; Thompson, C. B.; Jiang, X.
Article Title: Role of mitochondria in ferroptosis
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. © 2018 Elsevier Inc. Gao et al. show that mitochondria play a crucial and proactive role in cysteine-deprivation-induced ferroptosis but not in GPX4 inhibition-induced ferroptosis. Mechanistically, the mitochondrial TCA cycle and electron transport chain promote cysteine-deprivation-induced ferroptosis by serving as the major source for cellular lipid peroxide production. The anaplerotic role of glutaminolysis in replenishing the TCA cycle intermediates explains its involvement in cysteine-deprivation-induced ferroptosis. Importantly, mitochondria-mediated ferroptosis might contribute to the antitumor function of fumarate hydratase, a component of the TCA cycle and a tumor suppressor in renal cancer. © 2018 Elsevier Inc.
Journal Title: Molecular Cell
Volume: 73
Issue: 2
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2019-01-17
Start Page: 354
End Page: 363.e3
Language: English
DOI: 10.1016/j.molcel.2018.10.042
PUBMED: 30581146
PROVIDER: scopus
PMCID: PMC6338496
Notes: Export Date: 1 February 2019 -- Source: Scopus
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MSK Authors
  1. Xuejun Jiang
    78 Jiang
  2. Craig Bernie Thompson
    119 Thompson
  3. Prashant Monian
    7 Monian
  4. Minghui   Gao
    6 Gao
  5. Junmei Yi
    1 Yi
  6. Jiajun Zhu
    1 Zhu