State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
J Genet Genomics. 2023 May;50(5):318-329. doi: 10.1016/j.jgg.2023.03.005. Epub 2023 Mar 16.
Ferroptosis, a regulated and iron-dependent form of cell death characterized by peroxidation of membrane phospholipids, has tremendous potential for the therapy of human diseases. The causal link between phospholipid homeostasis and ferroptosis is incompletely understood. Here, we reveal that spin-4, a previously identified regulator of the "B12-one-carbon cycle-phosphatidylcholine (PC)" pathway, sustains germline development and fertility by ensuring PC sufficiency in the nematode Caenorhabditis elegans. Mechanistically, SPIN-4 regulates lysosomal activity which is required for B12-associated PC synthesis. PC deficiency-induced sterility can be rescued by reducing the levels of polyunsaturated fatty acids, reactive oxygen species, and redox-active iron, which indicates that the sterility is mediated by germline ferroptosis. These results highlight the critical role of PC homeostasis in ferroptosis susceptibility and offer a new target for pharmacological approaches.
铁死亡是一种受调控的、依赖于铁的细胞死亡形式，其特征是细胞膜磷脂的过氧化，在人类疾病的治疗中有巨大的潜力。磷脂稳态与铁死亡之间的因果关系尚未完全清楚。在这里，我们揭示了 spin-4，一种先前鉴定的“B12-一碳循环-磷脂酰胆碱 (PC)”途径的调节剂，通过确保线虫秀丽隐杆线虫中 PC 的充足来维持生殖系发育和生育能力。在机制上，SPIN-4 调节溶酶体活性，这是 B12 相关 PC 合成所必需的。通过降低多不饱和脂肪酸、活性氧和氧化还原活性铁的水平可以挽救由 PC 缺乏引起的不育，这表明不育是由生殖系铁死亡介导的。这些结果突出了 PC 稳态在铁死亡易感性中的关键作用，并为药理学方法提供了一个新的靶点。
