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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 ACTA2R179H and TGFBR2G357W 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.<\/jats:p>","DOI":"10.3390\/cells14110768","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T06:35:09Z","timestamp":1747982109000},"page":"768","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Defective Mitochondrial Respiration in Hereditary Thoracic Aneurysms"],"prefix":"10.3390","volume":"14","author":[{"given":"Daniel","family":"Marcos-R\u00edos","sequence":"first","affiliation":[{"name":"Laboratory of Vascular Pathology, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1456-2946","authenticated-orcid":false,"given":"Antonio","family":"Rochano-Ortiz","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerea","family":"M\u00e9ndez-Barbero","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Facultad de Medicina, Universidad Alfonso X el Sabio (UAX), Villanueva de la Ca\u00f1ada, 28691 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-2954","authenticated-orcid":false,"given":"Jorge","family":"Oller","sequence":"additional","affiliation":[{"name":"Laboratory of Vascular Pathology, Health Research Institute-Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital, Universidad Aut\u00f3noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Facultad de Medicina, Universidad Alfonso X el Sabio (UAX), Villanueva de la Ca\u00f1ada, 28691 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1161\/CIRCRESAHA.118.313187","article-title":"Cellular Mechanisms of Aortic Aneurysm Formation","volume":"124","author":"Quintana","year":"2019","journal-title":"Circ. 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