Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), Northeast Normal University, 5268 Renmin Street, Changchun, 130024, Jilin, China.
Nat Commun. 2024 Oct 17;15(1):8971. doi: 10.1038/s41467-024-53380-5.
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.
铁死亡是一种依赖于铁的细胞死亡方式，其中细胞膜上积累了铁依赖性脂质过氧化物。半胱氨酸是谷胱甘肽系统的一种限制底物，可中和脂质过氧化并防止铁死亡，它可以通过胱氨酸还原或从蛋氨酸合成。然而，越来越多的证据表明，在胱氨酸剥夺时，基于蛋氨酸的半胱氨酸合成不能有效地挽救细胞内半胱氨酸水平，并且不能抑制铁死亡。在这里，我们报告基于蛋氨酸的半胱氨酸合成是组织特异性的。出乎意料的是，我们发现，蛋氨酸实际上在胱氨酸剥夺诱导的铁死亡过程中发挥了重要作用，而不是抑制铁死亡。蛋氨酸衍生的 S-腺苷甲硫氨酸（SAM）有助于依赖于甲基化的泛醌合成，导致脂质过氧化物积累和随后的铁死亡。此外，SAM 补充与 Imidazole Ketone Erastin 在肿瘤生长抑制小鼠模型中协同作用。抑制将蛋氨酸转化为 SAM 的酶可保护心脏组织免受多柔比星诱导的和铁死亡驱动的心肌病。这项研究拓宽了我们对氨基酸代谢和铁死亡调控交叉的理解，深入了解了潜在的机制，并表明蛋氨酸-SAM 轴是治疗与铁死亡相关疾病的有前途的治疗策略。
