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Proteomic analysis of mitochondrial proteins in a mouse model of type 2 diabetes.

ABSTRACT: Impaired mitochondrial function may contribute to the onset of contractile dysfunction with insulin resistance/type 2 diabetes. Our aim was therefore to determine alterations in the mitochondrial proteome of a mouse model of obesity/type 2 diabetes.Mitochondrial proteins were isolated from hearts collected from 18- to 20-week-old female db/db mice and compared to matched controls. We performed two-dimensional polyacrylamide gel electrophoresis to determine differentially expressed proteins. Peptides of interest were further analysed by mass spectrometry and Mascot software was employed to identify protein matches.Our data showed that ATP synthase D chain, ubiquinol cytochrome-C reductase core protein 1 and electron transfer flavoprotein subunit alpha peptide levels were altered with obesity. Moreover, we found coordinate downregulation of contractile proteins in the obese heart, i.e. ?-smooth muscle actin, ?-cardiac actin, myosin heavy-chain ? and myosin-binding protein C.We propose that decreased contractile protein levels may contribute to contractile dysfunction of hearts from diabetic mice.

SUBMITTER: Essop MF

PROVIDER: S-EPMC3721950 | biostudies-literature | 2011 Jul-Aug

REPOSITORIES: biostudies-literature

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Proteomic analysis of mitochondrial proteins in a mouse model of type 2 diabetes.

Essop M F MF Chan W A WA Hattingh S S

Cardiovascular journal of Africa 20100911 4

<h4>Objective</h4>Impaired mitochondrial function may contribute to the onset of contractile dysfunction with insulin resistance/type 2 diabetes. Our aim was therefore to determine alterations in the mitochondrial proteome of a mouse model of obesity/type 2 diabetes.<h4>Methods</h4>Mitochondrial proteins were isolated from hearts collected from 18- to 20-week-old female db/db mice and compared to matched controls. We performed two-dimensional polyacrylamide gel electrophoresis to determine diffe ...[more]

PMID: 20859605

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Project description:OBJECTIVE The inability of pancreatic beta-cells to appropriately respond to glucose and secrete insulin are primary defects associated with beta-cell failure in type 2 diabetes. Mitochondrial dysfunction has been implicated as a key factor in the development of type 2 diabetes; however, a link between mitochondrial dysfunction and defective insulin secretion is unclear. RESEARCH DESIGN AND METHODS We investigated the changes in islet mitochondrial function and morphology during progression from insulin resistance (3 weeks old), immediately before hyperglycemia (5 weeks old), and after diabetes onset (10 weeks old) in transgenic MKR mice compared with controls. The molecular and protein changes at 10 weeks were determined using microarray and iTRAQ proteomic screens. RESULTS At 3 weeks, MKR mice were hyperinsulinemic but normoglycemic and beta-cells showed negligible mitochondrial or morphological changes. At 5 weeks, MKR islets displayed abrogated hyperpolarization of mitochondrial membrane potential (DeltaPsi(m)), reduced mitochondrial Ca(2+) uptake, slightly enlarged mitochondria, and reduced glucose-stimulated insulin secretion. By 10 weeks, MKR mice were hyperglycemic and hyperinsulinemic and beta-cells contained swollen mitochondria with disordered cristae. beta-Cells displayed impaired stimulus-secretion coupling including reduced hyperpolarization of DeltaPsi(m), impaired Ca(2+)-signaling, and reduced glucose-stimulated ATP/ADP and insulin release. Furthermore, decreased cytochrome c oxidase-dependent oxygen consumption and signs of oxidative stress were observed in diabetic islets. Protein profiling of diabetic islets revealed that 36 mitochondrial proteins were differentially expressed, including inner membrane proteins of the electron transport chain. CONCLUSIONS We provide novel evidence for a critical role of defective mitochondrial oxidative phosphorylation and morphology in the pathology of insulin resistance-induced beta-cell failure.

Dataset Information

Proteomic analysis of mitochondrial proteins in a mouse model of type 2 diabetes.

Publications

Proteomic analysis of mitochondrial proteins in a mouse model of type 2 diabetes.

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