Mitochondrial NAD+ Deficiency in Vascular Smooth Muscle Impairs Collagen III Turnover to Trigger Aortic Disease

Aortic disease poses a significant mortality risk in adults, yet many of its underlying factors remain undiscovered. In this study, we identify mitochondrial NAD⁺ deficiency as a causal factor. Metabolomics analysis of 73 surgical aortic specimens revealed impaired NAD⁺ salvage and mitochondrial transport in diseased aortas. Precursor metabolites NMN and NAM were significantly elevated, while NAD⁺ levels were decreased, indicating a disrupted salvage biosynthesis pathway. Using mouse models, we provided mechanistic insights into the pathogenic process. The production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid in collagen. A deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, impairs proline biosynthesis in mitochondria, potentially contributing to the progression of aortic disease.