2. Academic Validation
  3. Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake

Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake

  • J Clin Invest. 2025 Apr 1;135(7):e181928. doi: 10.1172/JCI181928.
Lu Sun 1 2,  Ruixue Leng 3,  Monan Liu 1,  Meiming Su 1,  Qingze He 1,  Zhidan Zhang 1,  Zhenghong Liu 1,  Zhihua Wang 1,  Hui Jiang 1,  Li Wang 4,  Shuai Guo 5,  Yiming Xu 5,  Yuqing Huo 6,  Clint L Miller 7,  Maciej Banach 8,  Yu Huang 4,  Paul C Evans 9,  Jaroslav Pelisek 10,  Giovanni G Camici 11,  Bradford C Berk 12,  Stefan Offermanns 13,  Junbo Ge 14,  Suowen Xu 1 13 15,  Jianping Weng 1 15 16
Affiliations

Affiliations

  • 1 Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 2 Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 3 Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
  • 4 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
  • 5 School of Basic Medical Sciences, State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 6 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
  • 7 Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
  • 8 Department of Preventive Cardiology and Lipidology, Medical University of Lodz (MUL), Lodz, Poland.
  • 9 Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
  • 10 Department of Vascular Surgery, University Hospital Zurich, Zurich, Switzerland.
  • 11 Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
  • 12 Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
  • 13 Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 14 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
  • 15 Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei, Anhui, China.
  • 16 Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
PMID: 40166941 DOI: 10.1172/JCI181928
Abstract

Mitochondrial dysfunction fuels vascular inflammation and atherosclerosis. Mitochondrial calcium uptake 1 (MICU1) maintains mitochondrial Ca2+ homeostasis. However, the role of MICU1 in vascular inflammation and atherosclerosis remains unknown. Here, we report that endothelial MICU1 prevents vascular inflammation and atherosclerosis by maintaining mitochondrial homeostasis. We observed that vascular inflammation was aggravated in endothelial cell-specific Micu1 knockout mice (Micu1ECKO) and attenuated in endothelial cell-specific Micu1 transgenic mice (Micu1ECTg). Furthermore, hypercholesterolemic Micu1ECKO mice also showed accelerated development of atherosclerosis, while Micu1ECTg mice were protected against atherosclerosis. Mechanistically, MICU1 depletion increased mitochondrial Ca2+ influx, thereby decreasing the expression of the mitochondrial deacetylase Sirtuin 3 (SIRT3) and the ensuing deacetylation of superoxide dismutase 2 (SOD2), leading to the burst of mitochondrial Reactive Oxygen Species (mROS). Of clinical relevance, we observed decreased MICU1 expression in the endothelial layer covering human atherosclerotic plaques and in human aortic endothelial cells exposed to serum from patients with coronary artery diseases (CAD). Two-sample Wald ratio Mendelian randomization further revealed that increased expression of MICU1 was associated with decreased risk of CAD and coronary artery bypass grafting (CABG). Our findings support MICU1 as an endogenous endothelial resilience factor that protects against vascular inflammation and atherosclerosis by maintaining mitochondrial Ca2+ homeostasis.

Keywords

Atherosclerosis; Cell biology; Vascular biology.

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