From mitochondrial zonation to immune dysregulation: a mechanistic axis in diabetic cardiomyopathy

Diabetic cardiomyopathy (DbCM) is characterized by early diastolic dysfunction, myocardial fibrosis, and progressive energetic failure, in which mitochondria dysfunction have a central role. Although mitochondrial dysfunction is well established in DbCM, emerging spatially resolved data indicate that cardiomyocytes contain functionally distinct mitochondrial subpopulations with differential susceptibility to metabolic stress. In this Review, we synthesize mechanistic and translational evidence and propose a unifying, testable hypothesis. Selective remodeling of membrane lipids and cristae destabilization may render specific mitochondrial subsets "early-damaged." These mitochondria produce sustained mitochondrial reactive oxygen species (mtROS), release oxidized mtDNA or mitochondrial-derived vesicles (MDVs), and subsequently activate innate immune pathways. We particularly emphasize distinct mitochondrial subpopulations, including subsarcolemmal (SSM), interfibrillar (IFM), and perinuclear mitochondria (PNM). Finally, we posit a proof-of-concept translational roadmap involving biomarker-guided, spatially informed preclinical endpoints and targeted interventions. Conceptualizing DbCM as a disease of mitochondrial heterogeneity and maladaptive mtROS-mtDNA-innate immune coupling reorients therapeutic strategy from global antioxidant suppression toward precision, organelle- and location-specific modulation.