Mitochondrial metabolic reprogramming in diabetic cardiomyopathy.

Diabetes mellitus represents a major global health challenge and is strongly associated with cardiovascular complications, among which diabetic cardiomyopathy (DCM) is a major contributor to heart failure. Increasing evidence indicates that mitochondrial dysfunction plays a central role in DCM pathogenesis. However, mitochondrial abnormalities in the diabetic heart reflect not merely cellular injury but a coordinated process of mitochondrial metabolic reprogramming, characterized by altered substrate utilization, impaired oxidative phosphorylation, and disruption of mitochondrial quality control. Under diabetic conditions, chronic hyperglycemia, insulin resistance, and lipid overload induce profound metabolic remodeling in cardiomyocytes. These disturbances promote excessive reactive oxygen species production, mitochondrial DNA damage, and dysfunction of the electron transport chain. Concurrently, cardiomyocytes undergo a shift in substrate preference, including enhanced glycolysis, dysregulated fatty acid oxidation, and altered amino acid metabolism. Such metabolic inflexibility compromises ATP production and contributes to lipotoxicity, oxidative stress, and cardiomyocyte apoptosis. Recent studies have revealed that mitochondrial metabolic reprogramming is governed by complex regulatory networks, including signaling pathways such as AMPK/PGC-1α, PI3K/Akt/mTOR, hypoxia-inducible factor-1α, and TGF-β/Smad, together with epigenetic mechanisms and mitochondrial quality control processes. Disruption of mitochondrial dynamics, mitophagy, and mitochondrial biogenesis further promotes the accumulation of dysfunctional mitochondria and accelerates disease progression. In this review, we summarize current advances in the mechanisms underlying mitochondrial metabolic reprogramming in diabetic cardiomyopathy and discuss emerging therapeutic strategies targeting mitochondrial metabolism. By integrating mitochondrial biology with cardiovascular metabolism, this review provides a comprehensive framework for understanding DCM pathogenesis and highlights potential directions for precision therapeutic intervention.