Optic Atrophy 1 (OPA1) overexpression promotes dyslipidemia and atherosclerosis coupled to altered aortic VSMC function in LDL-R deficient mice.

Aims: Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, sterol and bile acids (BAs) synthesis. Mitochondria are plastic organelles and continuously undergo biogenesis, fusion, fission and mitophagy. On these premises, we tested how the overexpression of OPA1, an inner mitochondrial membrane fusion protein, impacts lipids, lipoprotein metabolism and atherosclerosis development in LDL-R deficient mice (LDLR KO). Methods: OPA1TG/LDLR KO and OPA1ΔHep /LDLR KO were generated and fed with a Western-type diet (WTD) for 12 weeks. Atherosclerosis development was compared to that of LDLR KO mice. In humans, OPA1 expression was investigated in samples from 78 asymptomatic and symptomatic human subjects within the Carotid Plaque Imaging Project (CPIP). Results: OPA1TG/LDLR KO mice showed a significant increase in plasma cholesterol levels mainly in VLDL and LDL fractions. OPA1TG/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 affects also vascular smooth muscle cell cellular metabolism, leading to an increase in the synthetic vs the proliferative phenotype. Vice versa, hepatocyte deletion of OPA1 improved systemic lipoprotein metabolism and protected from atherosclerosis. The analysis of human atherosclerotic samples indicated that a higher OPA1 expression in the plaque is associated with a reduced degradation of extracellular matrix as well as the expression of markers of cell migration and differentiation. Conclusion: Mitochondrial fusion mediated by OPA1 plays a key role in atherosclerosis by affecting lipoprotein metabolism as well as vascular smooth muscle cell biology.

研究目的：线粒体参与细胞代谢、能量产生、钙稳态、固醇与胆汁酸（BAs）的合成过程。线粒体是一类具有可塑性的细胞器，持续进行生物发生、融合、分裂及线粒体自噬。基于上述背景，本研究探讨了视神经萎缩蛋白1（OPA1）——一种线粒体内膜融合蛋白——的过表达对低密度脂蛋白受体（LDL-R）缺陷小鼠（LDLR KO）的脂质、脂蛋白代谢及动脉粥样硬化发生发展的影响。
实验方法：构建OPA1过表达/LDLR敲除（OPA1TG/LDLR KO）及肝细胞特异性OPA1缺失/LDLR敲除（OPA1ΔHep/LDLR KO）小鼠模型，给予西方饮食（WTD）喂养12周，并将动脉粥样硬化的发生发展情况与单纯LDLR敲除小鼠进行对照分析。在人体样本层面，本研究依托颈动脉斑块成像项目（CPIP），对78名无症状及有症状受试者的样本开展了OPA1表达水平检测。
实验结果：OPA1TG/LDLR KO小鼠的血浆胆固醇水平显著升高，且升高主要集中于极低密度脂蛋白（VLDL）与低密度脂蛋白（LDL）组分。OPA1过表达可使小鼠体内游离胆汁酸水平降低，结合胆汁酸占比升高，进而促进脂质吸收。该表型与主动脉根部动脉粥样硬化病变加重相关。OPA1过表达还可调控血管平滑肌细胞的细胞代谢，使其合成型表型相较于增殖型表型更为突出。与之相反，肝细胞特异性OPA1敲除可改善全身脂蛋白代谢，减轻动脉粥样硬化损伤。对人体动脉粥样硬化样本的分析显示，斑块内较高的OPA1表达与细胞外基质降解减少、细胞迁移及分化标志物的表达水平降低密切相关。
研究结论：OPA1介导的线粒体融合通过影响脂蛋白代谢及血管平滑肌细胞生物学特性，在动脉粥样硬化的发生发展中发挥关键调控作用。