Dopaminylation of endothelial TPI1 suppresses ferroptotic angiocrine signals to promote lung regeneration over fibrosis

Chunheng Mo; Hui Li; Mengli Yan; Shiyu Xu; Jinyan Wu; Jiachen Li; Xinchun Yang; Yuanyuan Li; Jian Yang; Xingping Su; Jie Liu; Chuan Wu; Yuan Wang; Haohao Dong; Lu Chen; Lunzhi Dai; Ming Zhang; Qiang Pu; Liming Yang; Tinghong Ye; Zhongwei Cao; Bi-Sen Ding

doi:10.1016/j.cmet.2024.07.008

Dopaminylation of endothelial TPI1 suppresses ferroptotic angiocrine signals to promote lung regeneration over fibrosis

Cell Metab. 2024 Aug 6;36(8):1839-1857.e12. doi: 10.1016/j.cmet.2024.07.008.

Authors

Chunheng Mo¹, Hui Li¹, Mengli Yan¹, Shiyu Xu¹, Jinyan Wu¹, Jiachen Li¹, Xinchun Yang¹, Yuanyuan Li¹, Jian Yang¹, Xingping Su¹, Jie Liu¹, Chuan Wu¹, Yuan Wang¹, Haohao Dong¹, Lu Chen¹, Lunzhi Dai¹, Ming Zhang², Qiang Pu³, Liming Yang⁴, Tinghong Ye⁵, Zhongwei Cao⁶, Bi-Sen Ding⁷

Affiliations

¹ 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.
² 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. Electronic address: [email protected].
³ 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. Electronic address: [email protected].
⁴ Department of Pathophysiology, Harbin Medical University, Harbin, China. Electronic address: [email protected].
⁵ 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. Electronic address: [email protected].
⁶ 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. Electronic address: [email protected].
⁷ 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. Electronic address: [email protected].

PMID: 39111287
DOI: 10.1016/j.cmet.2024.07.008

Abstract

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.

Keywords: angiocrine factors; dopaminylation; endothelial cells; ferroptosis; glucose metabolism; lipid metabolism; lung fibrosis; lung regeneration; vascular niche.

MeSH terms

Animals
Endothelial Cells* / metabolism
Ferroptosis*
Humans
Lung* / metabolism
Lung* / pathology
Male
Mice
Mice, Inbred C57BL
Pulmonary Fibrosis / metabolism
Pulmonary Fibrosis / pathology
Regeneration
Signal Transduction
Triose-Phosphate Isomerase / metabolism

Substances

Triose-Phosphate Isomerase