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

Sun, L.; Leng, R.; He, Q.; Su, M.; Zhang, Z.; Liu, Z.; Wang, Z.; Jiang, H.; Liu, M.; Wang, L.; Huo, Y.; Miller, C. L.; Banach, M.; Huang, Y.; Evans, P. C.; Pelisek, J.; Camici, G. G.; Berk, B. C.; Offermanns, S.; Ge, J.; Xu, S.; Weng, J.

doi:10.1101/2024.08.22.609192

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bioRxiv · 10.1101/2024.08.22.609192

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

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Abstract

Atherosclerosis is triggered by endothelial activation and vascular inflammation, which is closely related to mitochondrial dysfunction. Mitochondrial calcium uptake 1 (MICU1), as the gatekeeper of mitochondrial Ca2+ homeostasis, is a critical player in mitochondrial function and implicated in a plethora of pathophysiological conditions. However, the role of MICU1 in the pathogenesis of vascular inflammation and atherosclerosis is unknown. We ask whether endothelial MICU1 can prevent vascular inflammation and atherosclerosis by maintaining mitochondrial homeostasis. We observed that vascular inflammation in response to LPS was aggravated in EC-specific Micu1 knockout mice (Micu1ECKO) and reduced in EC-specific Micu1 transgenic mice (Micu1ECTg). Furthermore, hypercholesterolemic Micu1ECKO mice also showed accelerated formation of atherosclerotic plaques, while Micu1ECTg mice protected against atherosclerosis. Mechanistically, MICU1 regulated mitochondrial Ca2+ influx, thereby reducing the expression of the mitochondrial deacetylase SIRT3 and the ensuing deacetylation of SOD2, leading to the burst of mitochondrial reactive oxygen species (mROS). Of clinical relevance, we identified decreased MICU1 level in endothelial layer of human atherosclerotic plaques, as well as in primary human aortic endothelial cells (HAECs) exposed to serum from patients with coronary artery diseases. Two-sample Wald ratio Mendelian randomization further revealed that increased expression of MICU1 was associated with decreased risk of coronary artery bypass grafting (CABG). Our findings unravel a critical and unrecognized role of MICU1 in preventing vascular inflammation and atherosclerosis by maintaining mitochondrial Ca2+ homeostasis.

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Sun, L., Leng, R., He, Q., Su, M., Zhang, Z., Liu, Z., Wang, Z., Jiang, H., Liu, M., Wang, L., Huo, Y., Miller, C. L., Banach, M., Huang, Y., Evans, P. C., Pelisek, J., Camici, G. G., Berk, B. C., Offermanns, S., Ge, J., Xu, S., Weng, J.. 2024-08-22. Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake. https://doi.org/10.1101/2024.08.22.609192

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