Mitochondrial Regulation of Ferroptosis

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2021 Jul 30

PMID 34328510

Citations 177

Authors

Boyi Gan

Affiliations

Soon will be listed here.

Abstract

Ferroptosis is a form of iron-dependent regulated cell death driven by uncontrolled lipid peroxidation. Mitochondria are double-membrane organelles that have essential roles in energy production, cellular metabolism, and cell death regulation. However, their role in ferroptosis has been unclear and somewhat controversial. In this Perspective, I summarize the diverse metabolic processes in mitochondria that actively drive ferroptosis, discuss recently discovered mitochondria-localized defense systems that detoxify mitochondrial lipid peroxides and protect against ferroptosis, present new evidence for the roles of mitochondria in regulating ferroptosis, and outline outstanding questions on this fascinating topic for future investigations. An in-depth understanding of mitochondria functions in ferroptosis will have important implications for both fundamental cell biology and disease treatment.

Citing Articles

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References

Kasukabe T, Honma Y, Okabe-Kado J, Higuchi Y, Kato N, Kumakura S . Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells. Oncol Rep. 2016; 36(2):968-76. DOI: 10.3892/or.2016.4867. View

Conrad M, Kagan V, Bayir H, Pagnussat G, Head B, Traber M . Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev. 2018; 32(9-10):602-619. PMC: 6004068. DOI: 10.1101/gad.314674.118. View

Eagle H . Nutrition needs of mammalian cells in tissue culture. Science. 1955; 122(3168):501-14. DOI: 10.1126/science.122.3168.501. View

Yant L, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter J . The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med. 2003; 34(4):496-502. DOI: 10.1016/s0891-5849(02)01360-6. View

Friedmann Angeli J, Schneider M, Proneth B, Tyurina Y, Tyurin V, Hammond V . Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014; 16(12):1180-91. PMC: 4894846. DOI: 10.1038/ncb3064. View

Jiang L, Kon N, Li T, Wang S, Su T, Hibshoosh H . Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015; 520(7545):57-62. PMC: 4455927. DOI: 10.1038/nature14344. View

Hou W, Xie Y, Song X, Sun X, Lotze M, Zeh 3rd H . Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016; 12(8):1425-8. PMC: 4968231. DOI: 10.1080/15548627.2016.1187366. View

Schneider M, Forster H, Boersma A, Seiler A, Wehnes H, Sinowatz F . Mitochondrial glutathione peroxidase 4 disruption causes male infertility. FASEB J. 2009; 23(9):3233-42. DOI: 10.1096/fj.09-132795. View

Wang Y, Chang S, Wu Q, Gou Y, Jia L, Cui Y . The Protective Role of Mitochondrial Ferritin on Erastin-Induced Ferroptosis. Front Aging Neurosci. 2017; 8:308. PMC: 5167726. DOI: 10.3389/fnagi.2016.00308. View

10.

Ye L, Chaudhary K, Zandkarimi F, Harken A, Kinslow C, Upadhyayula P . Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers. ACS Chem Biol. 2020; 15(2):469-484. PMC: 7180072. DOI: 10.1021/acschembio.9b00939. View

11.

Matsushita M, Freigang S, Schneider C, Conrad M, Bornkamm G, Kopf M . T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med. 2015; 212(4):555-68. PMC: 4387287. DOI: 10.1084/jem.20140857. View

12.

Koppula P, Zhuang L, Gan B . Cytochrome P450 reductase (POR) as a ferroptosis fuel. Protein Cell. 2021; 12(9):675-679. PMC: 8403093. DOI: 10.1007/s13238-021-00823-0. View

13.

Tait S, Oberst A, Quarato G, Milasta S, Haller M, Wang R . Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep. 2013; 5(4):878-85. PMC: 4005921. DOI: 10.1016/j.celrep.2013.10.034. View

14.

Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P . BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018; 20(10):1181-1192. PMC: 6170713. DOI: 10.1038/s41556-018-0178-0. View

15.

Lei G, Zhang Y, Hong T, Zhang X, Liu X, Mao C . Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity. Oncogene. 2021; 40(20):3533-3547. PMC: 8141034. DOI: 10.1038/s41388-021-01790-w. View

16.

Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K . Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell. 2018; 172(3):409-422.e21. DOI: 10.1016/j.cell.2017.11.048. View

17.

Linkermann A, Skouta R, Himmerkus N, Mulay S, Dewitz C, De Zen F . Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A. 2014; 111(47):16836-41. PMC: 4250130. DOI: 10.1073/pnas.1415518111. View

18.

Zhang Y, Swanda R, Nie L, Liu X, Wang C, Lee H . mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat Commun. 2021; 12(1):1589. PMC: 7952727. DOI: 10.1038/s41467-021-21841-w. View

19.

Koppula P, Zhang Y, Zhuang L, Gan B . Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun (Lond). 2018; 38(1):12. PMC: 5993148. DOI: 10.1186/s40880-018-0288-x. View

20.

Shin D, Lee J, You J, Kim D, Roh J . Dihydrolipoamide dehydrogenase regulates cystine deprivation-induced ferroptosis in head and neck cancer. Redox Biol. 2020; 30:101418. PMC: 6957841. DOI: 10.1016/j.redox.2019.101418. View