Abstract
Insulin resistance plays a major role in the development of type 2 diabetes and obesity and affects a number of biological processes such as mitochondrial biogenesis. Though mitochondrial dysfunction has been linked to the development of insulin resistance and pathogenesis of type 2 diabetes, the precise mechanism linking the two is not well understood. We used high fat diet (HFD)-induced obesity dependent diabetes mouse models to gain insight into the potential pathways altered with metabolic disease, and carried out quantitative proteomic analysis of liver mitochondria. As previously reported, proteins involved in fatty acid oxidation, branched chain amino acid degradation, tricarboxylic acid cycle, and oxidative phosphorylation were uniformly up-regulated in the liver of HFD fed mice compared with that of normal diet. Further, our studies revealed that retinol metabolism is distinctly down-regulated and the mitochondrial structural proteins-components of mitochondrial inter-membrane space bridging (MIB) complex (Mitofilin, Sam50, and ChChd3), and Tim proteins-essential for protein import, are significantly up-regulated in HFD fed mice. Structural and functional studies on HFD and normal diet liver mitochondria revealed remodeling of HFD mitochondria to a more condensed form with increased respiratory capacity and higher ATP levels compared with normal diet mitochondria. Thus, it is likely that the structural remodeling is essential to accommodate the increased protein content in presence of HFD: the mechanism could be through the MIB complex promoting contact site and crista junction formation and in turn facilitating the lipid and protein uptake.
Highlights
Obesity has become a global epidemic and in the United States alone more than one third of adults (34%) are obese and over 11% of the population over the age of 20 are diabetic [1, 2]
In our study we show that retinol metabolism was consistently down-regulated, and the proteins involved in the protein import into mitochondria, mitochondrial biogenesis and regulation of crista morphology are up-regulated in high fat diet (HFD) versus normal diet (ND) liver mitochondria
Proteomic Profiling of HFD/ND Mice Liver Mitochondria— To gain insights into mitochondrial dysfunction in liver under insulin resistance and type 2 diabetes (T2D) conditions, we analyzed the proteins and pathways altered by HFD in mouse liver mitochondria
Summary
T2D, type 2 diabetes; iTRAQ, isobaric tagging for relative and absolute quantification; HFD, high fat diet; ND, normal diet; ChChd, coiled-coil helix coiled-coil helix domain containing protein 3; FDR, false discovery rate; GO, gene ontology; mAb, monoclonal antibody; pAb, polyclonal antibody; PQD, pulsed Q dissociation; CAD, collision activated dissociation; EM, electron microscopy; OXPHOS, oxidative phosphorylation; MIB, mitochondrial intermembrane space bridging; MICOS, mitochondrial contact site. Proteomic Analysis of Type 2 Diabetic Liver Mitochondria adipose tissue, it has been shown that adiponectin expression and mitochondrial content in obese db/db mice were reduced [15]. Liver mitochondria showed significant up-regulation of beta-oxidation, branched chain amino acid degradation, pyruvate metabolism, TCA cycle, and apoptotic pathways [18, 19]. We used a proteomic approach to investigate the biological pathways leading to insulin resistance in T2D in the liver and analyzed the protein expression profiles from mitochondria of mice fed on a high fat diet (HFD) for 30 weeks. Consistent with previous studies, liver mitochondria showed significant up-regulation of oxidationphosphorylation (OXPHOS), beta-oxidation, branched chain amino acid degradation, pyruvate metabolism, TCA cycle, and apoptotic pathways [18, 19]. Our oxygen consumption experiment showed increased activities of complex I and complex II in liver mitochondria of HFD versus ND mice and our ATP assay confirmed increased ATP production in HFD versus ND mice
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