FAM177A1 disrupts SIRT3-SOD2 signaling to drive mitochondrial dysfunction-mediated VSMC phenotypic switching in...

Vascular remodeling involves structural and functional vascular changes in response to injury, aging, and disease. A key pathological feature is vascular smooth muscle cells (VSMCs) phenotypic switching, which is accompanied by mitochondrial dysregulation. Metabolic reprogramming resembling the Warburg effect alongside mitochondrial oxidative damage collectively drive this pathological VSMC transdifferentiation. We hypothesized that targeting mitochondrial ROS could restore mitochondrial integrity and enhance oxidative phosphorylation (OXPHOS) to counteract both oxidative damage and metabolic reprogramming in cardiovascular diseases associated with vascular remodeling. We proposed that the uncharacterized membrane-associated protein FAM177A1 drives VSMC mitochondrial oxidative impairment and metabolic reprogramming, thereby promoting VSMC phenotypic switching and vascular dysfunction.

We modeled vascular remodeling using global Fam177a1 knockout rats subjected to carotid balloon injury, VSMC-specific AAV-mediated Fam177a1 knockdown in carotid artery ligation mice, and using ApoE ^-/- mice fed a 12-week high-fat diet to induce atherosclerosis; in vitro VSMCs with platelet-derived growth factor-bb (PDGF-BB) stimulation further elucidated FAM177A1's role in phenotypic switching. FAM177A1 expression was significantly elevated in injured and atherosclerotic aortas, while its deficiency suppressed neointimal hyperplasia and atherosclerosis development. FAM177A1 deficiency upregulated mitochondrial functional genes, enhanced mtDNA biogenesis, reduced ROS accumulation, maintained redox homeostasis, and preserved mitochondrial membrane potential (ΔΨm). Moreover, FAM177A1 deficiency enhanced oxidative phosphorylation (OXPHOS) while reducing glycolytic flux, thereby improving bioenergetic efficiency and promoting a contractile phenotype. Molecular analysis revealed that FAM177A1 disrupted SIRT3-SOD2 binding, leading to elevated SOD2 K68 acetylation which decreased SOD2 activity and stability. Under pathological condition, this dysregulated cascade increased mitochondrial ROS, impaired mitochondrial function, thereby accelerating VSMC phenotypic switching.

We identify FAM177A1 as a key mitochondrial regulator that drives VSMC switching through SIRT3-SOD2 axis disruption. Targeting FAM177A1 restores redox-metabolic homeostasis through scavenging ROS and improving OXPHOS, establishing it as a novel therapeutic target against vascular remodeling.