Proteomic Analysis Suggests Altered Mitochondrial Metabolic Profile Associated With Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DbCM) occurs independently of cardiovascular diseases or hypertension, leading to heart failure and increased risk for death in diabetic patients. To investigate the molecular mechanisms involved in DbCM, we performed a quantitative proteomic profiling analysis in the left ventricle (LV) of type 2 diabetic mice. Six-month-old C57BL/6J-lepr/lepr (db/db) mice exhibited DbCM associated with diastolic dysfunction and cardiac hypertrophy. Using quantitative shotgun proteomic analysis, we identified 53 differentially expressed proteins in the LVs of db/db mice, majorly associated with the regulation of energy metabolism. The subunits of ATP synthase that form the F1 domain, and Cytochrome c1, a catalytic core subunit of the complex III primarily responsible for electron transfer to Cytochrome c, were upregulated in diabetic LVs. Upregulation of these key proteins may represent an adaptive mechanism by diabetic heart, resulting in increased electron transfer and thereby enhancement of mitochondrial ATP production. Conversely, diabetic LVs also showed a decrease in peptide levels of NADH dehydrogenase 1β subcomplex subunit 11, a subunit of complex I that catalyzes the transfer of electrons to ubiquinone. Moreover, the atypical kinase COQ8A, an essential lipid-soluble electron transporter involved in the biosynthesis of ubiquinone, was also downregulated in diabetic LVs. Our study indicates that despite attempts by hearts from diabetic mice to augment mitochondrial ATP energetics, decreased levels of key components of the electron transport chain may contribute to impaired mitochondrial ATP production. Preserved basal mitochondrial respiration along with the markedly reduced maximal respiratory capacity in the LVs of db/db mice corroborate the association between altered mitochondrial metabolic profile and cardiac dysfunction in DbCM.

Mitochondrial-derived Peptide Single-nucleotide Polymorphisms Associated with Cardiovascular Complications in Type 2 Diabetes

“…A second potential mediator of mitochondrial uncoupling is the adenine nucleotide translocator [68][69][70][71][72]. Various studies in animal and human models have frequently demonstrated mitochondrial damage at different levels in the diabetic myocardium [1,19,[73][74][75][76][77][78][79][80].…”

Transcriptomic and proteomic pathways of diabetic and non-diabetic mitochondrial transplantation

“…These differences are likely due to the decreased respiration competency of the diabetic ZDF-mitochondria and agree with the results of Gomes et al . 21 who demonstrated that downregulation of mitochondrial functional proteins in the diabetic heart with reduced levels of complex I protein subfractions that directly affect mitochondrial electron transport function. These findings are also supported by Mootha et al .…”

“…The observation that both non-diabetic ZL-mitochondria and diabetic ZDF-mitochondria downregulated immune response and inflammation pathways agrees with our previous findings demonstrating that the transplanted mitochondria do not induce any detectable organ-or systemic immune, autoimmune or inflammatory response. Enzyme-linked immunosorbent spot (ELISpot), enzyme-linked immunosorbent assay (ELISA), fluorescence-activated cell sorting (FACS) and multiplex analysis have failed to detect any immune or inflammatory effects associated with mitochondrial transplantation [6][7][8]21 . The effect of ROS in this study was not investigated, however, we have previously demonstrated that there is no increase in ROS associated with mitochondrial transplantation 6 .…”

Hox‐driven conditional immortalization of myeloid and lymphoid progenitors: Uses, advantages, and future potential

“…Proteomic analysis by liquid chromatography and mass spectrometry (LC–MS/MS) was performed as previously described 76 . In brief, peptides were analyzed on a Thermo Scientific Easy‐nLC 1200 System combined to an Orbitrap Fusion Lumos Tribrid mass spectrometer (Thermo Scientific) and operated with Xcalibur software (version 4.0.21.10).…”

“…Proteomic analysis by liquid chromatography and mass spectrometry (LC-MS/MS) was performed as previously described. 76 In brief, pep-…”