Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations

Abstract

Peer CJ, Callery PS, Hollander JM. Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations. Am J Physiol Heart Circ Physiol 296: H359 -H369, 2009. First published December 5, 2008 doi:10.1152/ajpheart.00467.2008.-Diabetic cardiomyopathy is the leading cause of heart failure among diabetic patients, and mitochondrial dysfunction has been implicated as an underlying cause in the pathogenesis. Cardiac mitochondria consist of two spatially, functionally, and morphologically distinct subpopulations, termed subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). SSM are situated beneath the plasma membrane, whereas IFM are embedded between myofibrils. The goal of this study was to determine whether spatially distinct cardiac mitochondrial subpopulations respond differently to a diabetic phenotype. Swiss-Webster mice were subjected to intraperitoneal injections of streptozotocin or citrate saline vehicle. Five weeks after injections, diabetic hearts displayed decreased rates of contraction, relaxation, and left ventricular developed pressures (P Ͻ 0.05 for all three). Both mitochondrial size (forward scatter, P Ͻ 0.01) and complexity (side scatter, P Ͻ 0.01) were decreased in diabetic IFM but not diabetic SSM. Electron transport chain complex II respiration was decreased in diabetic SSM (P Ͻ 0.05) and diabetic IFM (P Ͻ 0.01), with the decrease being greater in IFM. Furthermore, IFM complex I respiration and complex III activity were decreased with diabetes (P Ͻ 0.01) but were unchanged in SSM. Superoxide production was increased only in diabetic IFM (P Ͻ 0.01). Oxidative damage to proteins and lipids, indexed through nitrotyrosine residues and lipid peroxidation, were higher in diabetic IFM (P Ͻ 0.05 and P Ͻ 0.01, respectively). The mitochondria-specific phospholipid cardiolipin was decreased in diabetic IFM (P Ͻ 0.01) but not SSM. These results indicate that diabetes mellitus imposes a greater stress on the IFM subpopulation, which is associated, in part, with increased superoxide generation and oxidative damage, resulting in morphological and functional abnormalities that may contribute to the pathogenesis of diabetic cardiomyopathy. diabetes; free radical; mitochondria

Mitochondrial Morphology in Metabolic Diseases

“…Inefficient respiration from IFM fits with the loss of contractile force, as IFM juxtaposed to the sacromere supply ATP for motive force. Coordinates with these changes in diabetic cardiac IFM were enhanced ROS production and oxidative stress in the form of lipid modification (34). We have observed a similar fragmented phenotype of cardiac IFM with STZ-induced diabetes (Fig.…”

“…The Hollander lab examined DCM in this model 5 weeks after the development of elevated blood glucose levels (34). As anticipated, contractile function was impaired in the hearts of diabetic mice.…”

“…Aside from genetic models, chemical manipulation to ablate pancreatic b-cells has been used to induce a type 1 diabetic phenotype through STZ (34,73,96,141). The Hollander lab examined DCM in this model 5 weeks after the development of elevated blood glucose levels (34).…”

“…In this study, the investigators made a distinction between subpopulations of mitochondria in cardiac tissue, separating the IFM from SSM for assessment of mitochondrial function. Using a unique light scatter approach to determine both the size and internal complexity of isolated IFM and SSM, Dabkowski and colleagues determined that IFM recovered from diabetic cardiac tissue were smaller in size and retained less internal complexity than wild-type controls (34). This was not observed in the SSM samples.…”

Mitochondria in the pathogenesis of diabetes: a proteomic view

“…The two populations of mitochondria response differently to physiological stimuli including obesity, diabetes, aging, fasting, apoptosis, and ischemia-reperfusion injury (Lesnefsky et al, 2001;Suh et al, 2003;Ritov et al, 2005;Mollica et al, 2006). John M. Hollander's research group investigated thoroughly the differential response of the two populations of mitochondria in both T1DM and T2DM, using both biochemical and proteomic tools, and thus improved our under- standing of the role of different mitochondrial populations in the pathogenesis of diabetic cardiomyopathy (Dabkowski et al, 2009;Baseler et al, 2010;Dabkowski et al, 2010). Baseler and coworkers conducted the first mitochondrial proteomic research in the heart of STZ-induced diabetic mice to investigate the different response of the two mitochondrial populations to T1DM.…”