Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake
Lu Sun, … , Suowen Xu, Jianping Weng
Lu Sun, … , Suowen Xu, Jianping Weng
Published April 1, 2025
Citation Information: J Clin Invest. 2025;135(7):e181928. https://doi.org/10.1172/JCI181928.
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Research Article Cell biology Vascular biology

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

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.

Authors

Lu Sun, Ruixue Leng, Monan Liu, Meiming Su, Qingze He, Zhidan Zhang, Zhenghong Liu, Zhihua Wang, Hui Jiang, Li Wang, Shuai Guo, Yiming Xu, Yuqing Huo, Clint L. Miller, Maciej Banach, Yu Huang, Paul C. Evans, Jaroslav Pelisek, Giovanni G. Camici, Bradford C. Berk, Stefan Offermanns, Junbo Ge, Suowen Xu, Jianping Weng

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Figure 4

MICU1 regulates mitochondrial Ca2+ uptake and ROS production in ECs.

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MICU1 regulates mitochondrial Ca2+ uptake and ROS production in ECs. (A ...
(A and B) Dihydroethidium (DHE) staining of aortic sections from Micu1fl/fl mice or Micu1ECKO mice (A), Micu1WT mice or Micu1ECTg mice (B) treated with saline or LPS (10 mg/kg) for 6 hours (n = 6). Scale bars: 20 μm. (C) Flow cytometry analysis of mROS levels using MitoSOX (n = 4). (D and E) MitoSOX fluorescence in HAECs depleted of MICU1 (D, n = 5) or overexpressed MICU1 (E, n = 6). Scale bars: 20 μm. (F) OCR of HAECs transfected with siNC or siMICU1. ATP production-linked OCR was analyzed and quantified. (G) OCR of HAECs transfected with siNC or siMICU1 in the presence of LPS (1μg/ml, 16 hours). ATP production-linked OCR was analyzed and quantified. (H) Kinetics of [Ca2+]m in response to HT (50 μM) in HAECs treated with siNC or siMICU1 in the presence (siNC+LPS, n = 30 cells; siMICU1+LPS, n = 10 cells) or absence (siNC, n = 15 cells; siMICU1, n = 10 cells) of LPS (1μg/ml) for 6 hours. (I) Kinetics of [Ca2+]m in response to HT (50 μM) in HAECs treated with Ad-NC or Ad-MICU1 in the presence (Ad-NC+LPS, n = 11 cells; Ad-MICU1+LPS, n = 15 cells) or absence (Ad-NC, n = 8 cells; Ad-MICU1, n = 13 cells) of LPS (1μg/ml) for 6 hours. (J and K) Kinetics of [Ca2+]m in response to HT (50 μM) in HAECs treated with siNC or siMICU1 (J), Ad-NC, or Ad-MICU1 (K) in the presence or absence of TNF-α (10 ng/ml) for 6 hours (siNC, n = 10 cells; siNC+TNF-α, n = 14 cells; siMICU1+TNF-α, n = 20 cells; Ad-NC, n = 13 cells; Ad-NC +TNF-α, n = 16 cells; Ad-MICU1+TNF-α, n = 27 cells). Statistical analysis was performed by 2-way ANOVA followed by Bonferroni’s post hoc tests (A, B, D, and E) and Student’s t test (C, F, and G).