Work

Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice

Year: 2025

Type: article

Abstract: Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, and the synthesis of sterols and bile acids (BAs). Emerging evidence suggests that mitochondrial dynamics including biogenesis, fusion, fission, and mitophagy critically influence cardiometabolic diseases, yet their role in atherogenesis remain poorly understood. Mitochondrial fusion ensures metabolic flexibility and stress adaptation, processes highly relevant to lipid handling and vascular cell plasticity. OPA1, a key regulator of inner mitochondrial membrane fusion, has been implicated in metabolic remodeling and cellular stress responses. We therefore investigated whether modulation of OPA1 expression affects lipid homeostasis and plaque formation in LDL receptor-deficient (LDLR KO) mice and in human carotid atherosclerosis. OPA1 TG /LDLR KO and OPA1 ΔHep /LDLR KO were fed with a Western-type diet (WTD) for 12 weeks. The development of atherosclerosis was compared to that of LDLR KO mice. In humans, the impact of OPA1 was investigated in asymptomatic and symptomatic subjects from the Carotid Plaque Imaging Project (CPIP) biobank. OPA1 TG /LDLR KO mice showed a significant increase in plasma cholesterol levels mainly in VLDL and LDL fractions. OPA1 TG /LDLR KO display a reduction of unconjugated bile acids and higher percentage of conjugated bile acids leading to an increased lipid adsorption. This phenotype was associated with increased atherosclerosis in the aortic root. OPA1 overexpression also resulted in an altered vascular smooth muscle cell (VSMC) cellular metabolism and differentiation, promoting a shift from a contractile/synthetic phenotype toward a more proliferative and metabolically active state. Concordantly, the deletion of OPA1 in hepatocytes improved systemic lipoprotein metabolism protecting from atherosclerosis. Concordantly in humans, plaque OPA1 mRNA levels are associated with metabolic and smooth muscle cell related pathways. Mitochondrial fusion mediated by OPA1 plays a key role in atherosclerosis by affecting lipoprotein metabolism and vascular smooth muscle cell biology. OPA1 overexpression promotes atherosclerosis by impacting bile acids maturation in the liver thus increasing plasma cholesterol levels. Increased OPA1 expression also affects metabolic pathways in cells within the atherosclerotic plaque. • OPA1 overexpression alters hepatic lipid metabolism, leading to hypercholesterolemia and enhanced atherosclerosis development in LDLR knockout mice. • Hepatic OPA1 influences bile acid composition, increasing conjugated bile acids and reducing secondary cytotoxic unconjugated bile acids. • Atherosclerotic plaques from OPA1 TG /LDLR KO mice exhibit a less synthetic VSMC phenotype and lower matrix metalloproteinase expression. • OPA1 functions as both a systemic metabolic regulator and local vascular modulator, underscoring its complex role in cardiometabolic disease.

Source: Molecular Metabolism

DOI: 10.1016/j.molmet.2025.102256