Abstract Body: Mitochondrial dysfunction and oxidative injury are increasingly recognized as central contributors to medial degeneration and aortic dissection. Nicotinamide riboside (NR), a precursor of NAD+, enhances mitochondrial metabolism and attenuates oxidative stress in cardiovascular disease models. Whether NAD+ repletion can maintain mitochondrial resilience and protect the aortic wall during injury, however, remains unknown.

We performed a temporal analysis of mitochondrial remodeling, redox imbalance, and smooth muscle cell (SMC) injury in the β-aminopropionitrile (BAPN) model of thoracic aortic disease, with and without NR supplementation. BAPN induced a striking early hypermetabolic state in the proximal aorta, marked by elevated mitochondrial respiration, increased spare capacity, enhanced proton leak, expansion of mitochondrial content, and pronounced cytosolic and mitochondrial reactive oxygen species. Despite this apparent metabolic activation, mitochondrial quality-control pathways were disrupted, with reduced TFAM and TOM20 expression, altered mitophagy signaling, and dysregulated mitochondrial dynamics. By P32, mitochondrial respiration collapsed even though medial structure remained largely preserved, indicating that energetic failure precedes overt architectural deterioration.

NR repletion restored NAD+ levels and transiently improved mitochondrial efficiency, normalizing coupling and reducing oxidative stress, DNA damage, and apoptosis at early stages. However, these benefits were not sustained. By P35, NR failed to maintain mitochondrial biogenesis or mitophagy programs, and by P44, NR-treated and untreated BAPN mice exhibited comparable oxidative DNA lesions, γH2AX accumulation, and TUNEL positivity. NR delayed mortality but did not prevent aortic dilation, ECM disorganization, or rupture.

Aortic injury in the BAPN model is characterized by an early phase of mitochondrial hyperactivation followed by collapse of oxidative phosphorylation and redox-driven SMC loss. Although NAD+ repletion transiently stabilizes mitochondrial metabolism and attenuates oxidative injury, it fails to restore mitochondrial homeostasis or protect the aortic wall from structural degeneration. These findings highlight mitochondrial remodeling as an early and dynamic driver of aortic disease progression and underscore the need for therapeutic strategies that couple metabolic support with preservation of aortic structural integrity.