Abstract
Diabetic cardiomyopathy (dCM) is characterized by myocardial dysfunction in diabetes and reflects interacting metabolic, redox, calcium, inflammatory, fibrotic, and microvascular disturbances. Mitochondrial fission and fusion are not merely morphological endpoints; when uncoupled from mitophagic clearance and cristae maintenance, they contribute to energetic failure and cell-specific cardiac injury. This review synthesizes evidence from human diabetic myocardium and dCM-specific experimental models, while distinguishing direct fission-fusion evidence from broader mitochondrial quality-control findings. We summarize how glucolipotoxicity, impaired energy sensing, calcium entry, mechanosensing, innate immunity, epitranscriptomic regulation, and ubiquitin editing converge on dynamin-related protein 1 (DRP1)/ fission 1 (FIS1)/ mitochondrial fission factor (MFF) and mitofusin 1 (MFN1)/ mitofusin 2 (MFN2)/ optic atrophy 1 (OPA1) pathways. We further compare consequences in cardiomyocytes, cardiac fibroblasts, and coronary microvascular endothelial cells, including ATP depletion, oxidative stress, regulated cell death, fibrosis, and perfusion injury. Candidate interventions are organized according to whether they restrain pathological fission, restore MFN/OPA1-dependent fusion, or normalize mitophagic flux. Despite strong cellular and rodent evidence, direct clinical validation and pharmacodynamic biomarkers remain limited. Future progress will require human myocardial phenotyping, single-cell and spatial analyses,
in vivo
measurement of mitochondrial dynamics, cell-selective delivery, and standardized flux-based endpoints. The therapeutic goal should be restoration of adaptive mitochondrial dynamics rather than indiscriminate inhibition of fission or promotion of fusion.