Marcos-Ríos Daniel, Rochano-Ortiz Antonio, Méndez-Barbero Nerea, Oller Jorge
Laboratory of Vascular Pathology, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain.
Cells. 2025 May 23;14(11):768. doi: 10.3390/cells14110768.
Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging evidence suggests the key role of mitochondrial dysfunction. Here, we show that the overexpression of and in murine aortic VSMCs reduces Mitochondrial Transcription Factor A (Tfam) expression, decreases mitochondrial DNA (mtDNA) content, and impairs oxidative phosphorylation, shifting metabolism toward glycolysis. Notably, nicotinamide riboside, a NAD precursor, restores mitochondrial respiration, increases Tfam and mtDNA levels, and promotes a contractile phenotype by enhancing actin polymerization and reducing matrix metalloproteinase activity. These findings identify mitochondrial dysfunction as a shared feature in hereditary thoracic aortic aneurysm, not only in Marfan syndrome, but also in other genetic forms, and highlight mitochondrial boosters as a potential therapeutic strategy.
胸主动脉瘤是与遗传性疾病相关的危及生命的血管疾病，如马凡综合征、洛伊迪茨综合征、血管性埃勒斯-当洛综合征以及家族性胸主动脉瘤和夹层。虽然传统上认为与细胞外基质和血管平滑肌细胞的收缩缺陷有关，但新出现的证据表明线粒体功能障碍起关键作用。在此，我们表明在小鼠主动脉血管平滑肌细胞中过表达[具体基因]会降低线粒体转录因子A（Tfam）的表达，减少线粒体DNA（mtDNA）含量，并损害氧化磷酸化，使代谢转向糖酵解。值得注意的是，烟酰胺核糖（一种NAD前体）可恢复线粒体呼吸，增加Tfam和mtDNA水平，并通过增强肌动蛋白聚合和降低基质金属蛋白酶活性来促进收缩表型。这些发现表明线粒体功能障碍是遗传性胸主动脉瘤的一个共同特征，不仅在马凡综合征中如此，在其他遗传形式中也是如此，并突出了线粒体增强剂作为一种潜在的治疗策略。
