Defective Mitochondrial Respiration in Hereditary Thoracic Aneurysms

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 extracellular matrix and contractile defects in vascular smooth muscle cells, emerging evidence suggests a key role for mitochondrial dysfunction. Here, we show that 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 strategies.