Methionine-SAM metabolism-dependent ubiquinone synthesis is crucial for ROS accumulation in ferroptosis induction

Chaoyi Xia, Pinghui Peng, Wenxia Zhang, Xiyue Xing, Xin Jin, Jianlan Du, Wanting Peng, Fengqi Hao, Zhexuan Zhao, Kejian Dong, Miaomiao Tian, Yunpeng Feng, Xueqing Ba (), Min Wei () and Yang Wang ()
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Chaoyi Xia: Northeast Normal University
Pinghui Peng: Northeast Normal University
Wenxia Zhang: Northeast Normal University
Xiyue Xing: Northeast Normal University
Xin Jin: Northeast Normal University
Jianlan Du: Northeast Normal University
Wanting Peng: Northeast Normal University
Fengqi Hao: Northeast Normal University
Zhexuan Zhao: Northeast Normal University
Kejian Dong: Northeast Normal University
Miaomiao Tian: Northeast Normal University
Yunpeng Feng: Northeast Normal University
Xueqing Ba: Northeast Normal University
Min Wei: Northeast Normal University
Yang Wang: Northeast Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Ferroptosis is a cell death modality in which iron-dependent lipid peroxides accumulate on cell membranes. Cysteine, a limiting substrate for the glutathione system that neutralizes lipid peroxidation and prevents ferroptosis, can be converted by cystine reduction or synthesized from methionine. However, accumulating evidence shows methionine-based cysteine synthesis fails to effectively rescue intracellular cysteine levels upon cystine deprivation and is unable to inhibit ferroptosis. Here, we report that methionine-based cysteine synthesis is tissue-specific. Unexpectedly, we find that rather than inhibiting ferroptosis, methionine in fact plays an essential role during cystine deprivation-induced ferroptosis. Methionine-derived S-adenosylmethionine (SAM) contributes to methylation-dependent ubiquinone synthesis, which leads to lipid peroxides accumulation and subsequent ferroptosis. Moreover, SAM supplementation synergizes with Imidazole Ketone Erastin in a tumor growth suppression mouse model. Inhibiting the enzyme that converts methionine to SAM protects heart tissue from Doxorubicin-induced and ferroptosis-driven cardiomyopathy. This study broadens our understanding about the intersection of amino acid metabolism and ferroptosis regulation, providing insight into the underlying mechanisms and suggesting the methionine-SAM axis is a promising therapeutic strategy to treat ferroptosis-related diseases.

Date: 2024
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DOI: 10.1038/s41467-024-53380-5

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