Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Lab of Biotherapy, State Key Laboratory of Respiratory Health and Multimorbidity, NHC Key Laboratory of Chronobiology, Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization, Development and Related Disease of Women and Children Key Lab of Sichuan, West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu, China.
Department of General Surgery, Department of Thoracic Surgery and Institute of Thoracic Oncology, Laboratory of Gastrointestinal Cancer and Liver Disease, West China Hospital, Sichuan University, Chengdu, China.
Cell Metab. 2024 Aug 6;36(8):1839-1857.e12. doi: 10.1016/j.cmet.2024.07.008.
Lungs can undergo facultative regeneration, but handicapped regeneration often leads to fibrosis. How microenvironmental cues coordinate lung regeneration via modulating cell death remains unknown. Here, we reveal that the neurotransmitter dopamine modifies the endothelial niche to suppress ferroptosis, promoting lung regeneration over fibrosis. A chemoproteomic approach shows that dopamine blocks ferroptosis in endothelial cells (ECs) via dopaminylating triosephosphate isomerase 1 (TPI1). Suppressing TPI1 dopaminylation in ECs triggers ferroptotic angiocrine signaling to aberrantly activate fibroblasts, leading to a transition from lung regeneration to fibrosis. Mechanistically, dopaminylation of glutamine (Q) 65 residue in TPI1 directionally enhances TPI1's activity to convert dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate (GAP), directing ether phospholipid synthesis to glucose metabolism in regenerating lung ECs. This metabolic shift attenuates lipid peroxidation and blocks ferroptosis. Restoring TPI1 Q65 dopaminylation in an injured endothelial niche overturns ferroptosis to normalize pro-regenerative angiocrine function and alleviate lung fibrosis. Overall, dopaminylation of TPI1 balances lipid/glucose metabolism and suppresses pro-fibrotic ferroptosis in regenerating lungs.
肺可以进行适应性再生，但受损的再生常常导致纤维化。微环境线索如何通过调节细胞死亡来协调肺再生仍然未知。在这里，我们揭示了神经递质多巴胺通过修饰内皮细胞龛来抑制铁死亡，从而促进肺再生而不是纤维化。化学蛋白质组学方法表明，多巴胺通过多巴胺化磷酸丙糖异构酶 1（TPI1）来阻断内皮细胞（ECs）中的铁死亡。抑制 ECs 中的 TPI1 多巴胺化会触发铁死亡的血管分泌信号，异常激活成纤维细胞，导致从肺再生到纤维化的转变。在机制上，TPI1 中谷氨酰胺（Q）65 残基的多巴胺化定向增强了 TPI1 的活性，将二羟丙酮磷酸（DHAP）转化为 3-磷酸甘油醛（GAP），将醚磷脂合成引导至再生肺 ECs 中的葡萄糖代谢。这种代谢转变减弱了脂质过氧化并阻止了铁死亡。在受损的内皮龛中恢复 TPI1 Q65 多巴胺化可逆转铁死亡，使促再生的血管分泌功能正常化并减轻肺纤维化。总的来说，TPI1 的多巴胺化平衡了脂质/葡萄糖代谢，并抑制了再生肺中的促纤维化铁死亡。
