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

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

doi:10.1172/JCI181928

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

Lu Sun (Co-first Author), Ruixue Leng (Co-first Author), 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. BerkStefan Offermanns, Junbo Ge, Suowen Xu^*, Jianping Weng^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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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 (Micu1^ECKO) and attenuated in endothelial cell–specific Micu1 transgenic mice (Micu1^ECTg). Furthermore, hypercholesterolemic Micu1^ECKO mice also showed accelerated development of atherosclerosis, while Micu1^ECTg 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. © 2025, Sun et al.

Original language	English
Article number	e181928
Journal	Journal of Clinical Investigation
Volume	135
Issue number	7
Online published	1 Apr 2025
DOIs	https://doi.org/10.1172/JCI181928
Publication status	Published - 1 Apr 2025

Funding

The authors thank the researchers and institutions who shared their data and all participants involved in this study. We also want to acknowledge the participants and investigators of the FinnGen study. This study was supported by grants from the National Key R&D Program of China (grant no. 2021YFC2500500), the National Natural Science Foundation of China (grant nos. 82003741, 82070464, 82370444, 12411530127), USTC Research Funds of the Double First-Class Initiative (YD9110002089), and the Hong Kong Research Grants Council (grant T12-101/23-N, SRFS2021-4S04). This work was also supported by the Program for Innovative Research Team of The First Affiliated Hospital of USTC (CXGG02) and the Anhui Provincial Natural Science Foundation (grant no. 2208085J08). PCE was supported by the British Heart Foundation (RG/19/10/34506). PCE made a significant contribution to analyzing and interpreting the data and reviewed the manuscript for important intellectual content. SX is a recipient of a Humboldt Research Fellowship from the Alexander von Humboldt Foundation, Germany.

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Sun, L., Leng, R., Liu, M., Su, M., He, Q., Zhang, Z., Liu, Z., Wang, Z., Jiang, H., Wang, L., Guo, S., Xu, Y., Huo, Y., Miller, C. L., Banach, M., Huang, Y., Evans, P. C., Pelisek, J., Camici, G. G., ... Weng, J. (2025). Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake. Journal of Clinical Investigation, 135(7), Article e181928. https://doi.org/10.1172/JCI181928

@article{7bc5125298b14b7d89c45bd4e19955b8,

title = "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. {\textcopyright} 2025, Sun et al.",

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

year = "2025",

month = apr,

day = "1",

doi = "10.1172/JCI181928",

language = "English",

volume = "135",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "7",

}

Sun, L, Leng, R, Liu, M, Su, M, He, Q, Zhang, Z, Liu, Z, Wang, Z, Jiang, H, Wang, L, Guo, S, Xu, Y, Huo, Y, Miller, CL, Banach, M, Huang, Y, Evans, PC, Pelisek, J, Camici, GG, Berk, BC, Offermanns, S, Ge, J, Xu, S & Weng, J 2025, 'Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake', Journal of Clinical Investigation, vol. 135, no. 7, e181928. https://doi.org/10.1172/JCI181928

Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake. / Sun, Lu (Co-first Author); Leng, Ruixue (Co-first Author); Liu, Monan et al.
In: Journal of Clinical Investigation, Vol. 135, No. 7, e181928, 01.04.2025.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake

AU - Sun, Lu

AU - Leng, Ruixue

AU - Liu, Monan

AU - Su, Meiming

AU - He, Qingze

AU - Zhang, Zhidan

AU - Liu, Zhenghong

AU - Wang, Zhihua

AU - Jiang, Hui

AU - Wang, Li

AU - Guo, Shuai

AU - Xu, Yiming

AU - Huo, Yuqing

AU - Miller, Clint L.

AU - Banach, Maciej

AU - Huang, Yu

AU - Evans, Paul C.

AU - Pelisek, Jaroslav

AU - Camici, Giovanni G.

AU - Berk, Bradford C.

AU - Offermanns, Stefan

AU - Ge, Junbo

AU - Xu, Suowen

AU - Weng, Jianping

PY - 2025/4/1

Y1 - 2025/4/1

N2 - 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. © 2025, Sun et al.

AB - 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. © 2025, Sun et al.

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DO - 10.1172/JCI181928

M3 - RGC 21 - Publication in refereed journal

C2 - 40166941

SN - 0021-9738

VL - 135

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 7

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ER -

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

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TBRS: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

SRFS: Systemic Benefits of Physical Activity: Crosstalk between Organs on Signal Transduction from Mechano-stimulation to Metabolism

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

Abstract

Funding

Publisher's Copyright Statement

UN SDGs

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Other Access Options

Permanent Link

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TBRS: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

SRFS: Systemic Benefits of Physical Activity: Crosstalk between Organs on Signal Transduction from Mechano-stimulation to Metabolism

Cite this