Proteomic Signatures of Cardiac Mitochondrial Remodelling During Acute Diabetes Reflect Metabolic and Redox Adaptations

Background: Mitochondria play a central role in cardiac energy metabolism and dynamically adapt to changes in metabolic demand. However, the early mitochondrial adaptations accompanying the acute phase of diabetes mellitus remain insufficiently understood. This study aimed to characterise diabetes-induced mitochondrial remodelling in the rat heart. Methods: Diabetes was induced using an established streptozotocin-induced rat model. Cardiac mitochondrial proteomes were analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS) in control and diabetic animals. Differential protein abundance was assessed by statistical comparison between groups using the limma package in R, and machine learning classification was used to identify proteins with the strongest discriminatory power between control and diabetic states. Results: Diabetes was associated with distinct mitochondrial proteomic remodelling. In the diabetic group, monoamine oxidase A (AOFA, padjust = 0.003) was markedly upregulated, fatty acid β-oxidation-related enzymes including dienoyl-CoA isomerase (ECH1, padjust < 0.001) and dienoyl-CoA reductase (DECR, padjust = 0.003) showed increased abundance, and respiratory chain complex I components, particularly NADH-ubiquinone oxidoreductase 75 kDa subunit (NDUS1, padjust = 0.016) and NADH dehydrogenase [ubiquinone] iron-sulfur protein 2 (NDUS2, padjust = 0.016), were elevated. Machine learning analysis consistently identified AOFA and key metabolic proteins as the strongest discriminators between diabetic and control animals (n = 6 per group). These changes indicate a coordinated shift towards enhanced lipid utilisation, altered mitochondrial respiratory function, and involvement of redox-associated processes. Conclusions: The observed proteomic changes may reflect early adaptive and compensatory mechanisms supporting mitochondrial function under increased energetic and oxidative load and highlight pathways that may represent promising candidates for targeted therapeutic modulation in diabetic cardiac dysfunction.