Nutrient stress-driven ACSS1 controls metabolic flexibility and bone formation

Metabolic dysregulation under nutrient stress disrupts bone homeostasis. Although acetate metabolism is linked to diabetes and alcoholism, its role in the skeletal complications of these conditions remains unknown. Here we identify acetyl-CoA synthetase 1 (ACSS1) as a key stress responder that mediates mitonuclear communication in bone marrow skeletal stem cells. ACSS1-driven rewiring of acetate metabolism impairs cellular metabolic flexibility, mitochondrial function, and osteogenesis. Mechanistically, nutrient excess from glucose, alcohol or acetate upregulates ACSS1 via a mitochondrial ROS activated integrated stress response-CEBPB pathway. Maladaptive ACSS1 accumulation enforces excessive acetyl-CoA production from either exogenous or glucose/ethanol-derived endogenous acetate, promoting mitochondrial protein hyperacetylation specifically inactivating ME2 via lysine 94 acetylation. This ACSS1-triggered ME2 inactivation disturbs the malate-aspartate shuttle, leading to a self-perpetuating cycle of redox imbalance and oxidative stress that exacerbates mitochondrial dysfunction and osteogenic impairment. Importantly, genetic deletion of Acss1 or AAV-delivered non-acetylatable ME2 mutant in osteoprogenitor cells restores mitochondrial resilience, osteogenic capacity, and bone formation, protecting against osteoporosis or osteonecrosis in male mouse models of type 2 diabetes and chronic alcohol consumption. These results unveil an essential role for ACSS1 in controlling metabolic flexibility and osteogenesis, identifying ACSS1 as a potential therapeutic target for metabolic stress-related bone disorders. ACSS1 mediates maladaptive mitonuclear communication under nutrient stress, impairing metabolic flexibility and osteogenesis. Targeting ACSS1 preserves bone integrity in diabetic and alcoholic mice by sustaining bone formation.