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  3. Cholesterol induced-mitochondrial calcium dysregulation facilitates atherosclerosis by promoting lipid accumulation in vascular smooth muscle cells

Cholesterol induced-mitochondrial calcium dysregulation facilitates atherosclerosis by promoting lipid accumulation in vascular smooth muscle cells

  • Mol Biomed. 2025 Dec 2;6(1):129. doi: 10.1186/s43556-025-00384-2.
Zhiwang Zhang 1,  Fan Yang 2,  Wei Wang 1,  Qi Cao 1,  Long Zhang 1,  Yu Zhang 1,  Dong Ma 1,  Xinhua Zhang 1,  Jinkun Wen 3,  Bin Zheng 4 5
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China.
  • 2 College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
  • 3 Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China. [email protected].
  • 4 Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China. [email protected].
  • 5 Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, Hebei Medical University, Shijiazhuang, 050017, China. [email protected].
PMID: 41329250 DOI: 10.1186/s43556-025-00384-2
Abstract

Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the pathogenesis of cardiovascular diseases. However, the relationship between mitochondrial calcium homeostasis in vascular smooth muscle cells (VSMCs) and atherosclerosis remains poorly understood. Here, we demonstrate that Cholesterol induces mitochondrial calcium overload and lipid accumulation in VSMCs, which is resulted from dysregulation of mitochondrial calcium uniporter (MCU), as evidenced by genetic and pharmacologic inhibition of MCU. Furthermore, MCU inhibitors alleviate Western diet-induced atherosclerosis in ApoE-/- mice. Mechanistically, high-fat and high-cholesterol diets induce the contact between mitochondria and the endoplasmic reticulum (ER) in VSMCs as indicated by transmission electron microscopy, proximity ligation assay and immunofluorescence staining, which increases the formation of mitochondria-associated membranes (MAMs), leading to Ca2 + release from the ER into the mitochondria and thus elevating Ca2 + in the mitochondria. Using mitochondrial calcium uptake 1 (MICU1) mutant and Ca2 + detection assay, we confirmed that this increased Ca2 + binds to MICU1, a blocker of MCU, to impair its ability to block MCU, thus enabling the MCU to remain open and resulting in mitochondrial calcium overload. Further, mitochondrial calcium overload dysregulates fatty acid β-oxidation by modulating medium-chain acyl-CoA dehydrogenase (ACADM), thereby leading to lipid deposition. The inhibition of MCU alleviates the pathological changes elecited by Cholesterol. Our findings unveil the previously unrecognized role of MAM-MICU1-MCU axis in cholesterol-induced mitochondrial calcium overload and atherosclerosis, indicating that MCU represents a promising therapeutic target for the treatment of atherosclerosis.

Keywords

Atherosclerosis; MCU inhibitor; MICU1; Mitochondrial calcium.

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