Integrative Proteomic and Bioenergetic Profiling Reveals Diet- and Strain-Specific Mitochondrial Dysfunction in Cohen Diabetic Rat Hearts

Mitochondrial dysfunction contributes to diabetic cardiomyopathy, yet how genetic predisposition and diet interact to reshape cardiac metabolism in diabetic and prediabetic states remains unclear. The Cohen diabetic rat model, comprising diabetes-resistant (CDr) and diabetes-sensitive (CDs) strains, provides a unique platform to dissect this interplay. Here, we present an integrative global proteomic and bioenergetic characterization of cardiac tissue from CDr and CDs rats fed either a regular or a diabetogenic diet. Proteomic pathway mapping revealed downregulation of cytochrome <i>c</i> oxidase (C<i>c</i>O) subunits, strain-dependent rewiring of fatty-acid oxidation pathways, and C<i>c</i>O subunits switch from "heart-type" to "liver-type" isoforms in the sensitive strain. These changes were accompanied by impaired mitochondrial respiration, ATP depletion, and disruption of mitochondrial quality-control mechanisms, together with increased accumulation of tyrosine 304 phosphorylation of cytochrome <i>c</i> oxidase subunit I, indicative of inflammation-driven regulatory inhibition in a diet-specific manner. These findings establish an understanding of how genetic susceptibility and diet contribute to cardiac mitochondrial dysfunction in the Cohen diabetic rat model.