Proteomic Analysis Suggests Altered Mitochondrial Metabolic Profile in Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DCM) occurs independently of coronary artery disease or hypertension, often leading to heart failure and death. Although remarkable progress has been made in recent years, there is still no specific therapy for myocardial damage induced by DCM, mainly due to its unclear molecular basis. To elucidate the molecular mechanisms involved in the DCM progress, we have performed advanced proteomic profiling analysis of heart tissue samples from the membrane‐bound leptin receptor deficient ( db/db ) mice, a widely used murine model of type 2 diabetes. As previously shown by our research group, db/db mice exhibit clinically relevant DCM phenotype by 6 months of age that includes diastolic dysfunction, cardiac hypertrophy, and cardiac fibrosis. Six‐month‐old C57BL/6J‐lepr/lepr ( db/db ) and C57BL/6J (wild type [WT]) male mice were euthanized, and the left ventricle (LV) was appropriately collected and processed for proteomic analysis. By shotgun proteomics performed after dimethyl labelling, we identified 77 differentially expressed proteins in LV of db/db mice. Among these, 27 proteins were downregulated in response to chronic diabetes, while 50 were upregulated. Many of these proteins were associated with energy metabolism, cytoskeleton organization, and calcium handling. The peptide levels of subunits alpha, beta and delta of ATP synthase were upregulated in the LVs of db/db mice. These subunits are arranged to form the F1 domain, a catalytic assembly of the enzyme. We also found a marked induction of cytochrome c1 in db/db mice, which is a catalytic core subunit of the complex III, responsible for electron transfer to cytochrome c. We propose that this may represent an adaptive mechanism by which the diabetic heart attempts to increase electron transfer and thereby enhance mitochondrial ATP production. Conversely, in db/db mice we found a decrease in peptide levels of NADH dehydrogenase 1 beta subcomplex subunit 11, a subunit of complex I that catalyzes transfer of electrons to ubiquinone. In diabetic hearts, we also found a downregulation of atypical kinase COQ8A, an essential lipid‐soluble electron transporter involved in the biosynthesis of ubiquinone. These data suggest that despite attempts by hearts from the diabetic mice to augment mitochondrial ATP production, decreased levels of key components of the electron transport chain may contribute to impaired mitochondrial ATP production. It is likely that ATP synthase subunits and cytochrome c1 may also be downregulated with prolonged persistence of the diabetic phenotype. Our study suggests that diabetic hearts displayed altered expression of mitochondrial metabolic peptides, which may contribute to the progression of DCM in db/db mice.

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