Macrophage MERTK restrains GRAMD1A-driven mitochondrial oxysterol trafficking to limit colitis
macrophages. Mechanistically, MERTK loss enhances cholesterol biosynthesis in the endoplasmic reticulum (ER) and stabilizes the cholesterol transporter GRAMD1A. This promotes excessive cholesterol trafficking from the ER to mitochondria. Within mitochondria, this cholesterol is metabolized into specific oxysterols that, unlike other mevalonate pathway metabolites, directly impair the electron transport chain. This impairment triggers a burst of mitochondrial reactive oxygen species (ROS). Collectively, our findings define a pathogenic axis linking defective efferocytosis, dysregulated cholesterol metabolism, and oxysterol-induced mitochondrial damage.
Authors
- Xiuwen Wu (ORCID: https://orcid.org/0000-0002-3813-3867)
- Juanhan Liu (ORCID: https://orcid.org/0000-0002-2442-679X)
- Tao Zheng (ORCID: https://orcid.org/0000-0002-4845-1295)
- Fansen Lin
- Wenbin Gong (ORCID: https://orcid.org/0000-0002-1699-9213)
- Xuanheng Li (ORCID: https://orcid.org/0000-0003-2606-6932)
- Cunxia Wu
- Jinyao Liu (ORCID: https://orcid.org/0000-0002-6044-2033)
- Peizhao Liu (ORCID: https://orcid.org/0000-0002-6996-6386)
- Jianan Ren (ORCID: https://orcid.org/0000-0002-4697-4762)
- Yangguang Li (ORCID: https://orcid.org/0000-0002-2453-6083)
- Qianwen Li (ORCID: https://orcid.org/0000-0002-5553-227X)
- Zexing Lin
- Guiwen Qu
- Yun Zhao
- Ze Li
- Yiyu Yang
Institutions
- Fujian Medical University (CN)
- Shanghai Mental Health Center (CN)
- First Affiliated Hospital of Fujian Medical University (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Jinling Institute of Technology (CN)
- Southeast University (CN)
- Nanjing Medical University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Redox Biology
- Published
- 2026-04-20
- DOI
- https://doi.org/10.1016/j.redox.2026.104174
- Primary Topic
- Cholesterol and Lipid Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00