Páginas: 8 (1934 palabras) Publicado: 8 de noviembre de 2010
Mitochondrial Networking Protects β-Cells From Nutrient-Induced Apoptosis

Anthony J.A. Molina,1 Jakob D. Wikstrom,1,2 Linsey Stiles,1,3 Guy Las,1 Hibo Mohamed,3 Alvaro Elorza,1 Gil Walzer,3 Gilad Twig,1 Steve Katz,3 Barbara E. Corkey,1 and Orian S. Shirihai1
1Department of Molecular Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts;
2TheWenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden;
3Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts.
Corresponding author: Orian S. Shirihai, Email:
Received December 18, 2006; Accepted June 18, 2009.
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Mitochondria mediate β-cell responses to extracellular glucose by generating ATP and initiating a cascade of events culminating in the release of insulin. It is not surprising that β-cell mitochondria have become an important target for investigationsinto the etiology of type 2 diabetes. Mitochondria are highly dynamic organelles whose morphology is regulated by cycles of fusion and fission, collectively termed mitochondrial dynamics (1,2). Networks are formed when mitochondria undergo fusion events that cause the compartments of participating mitochondria to become continuous. As a result, the constituents of each network share solutes,metabolites, and proteins (3–5) as well as a transmembrane electrochemical gradient (1,6). The disruption of such networks has been shown to have a profound effect on the progression of cells to apoptosis, particularly in cases where reactive oxygen species (ROS) are involved (7). As such, mitochondrial networking is thought to be a potential defense mechanism allowing for the buffering of mitochondrialROS and calcium overload (8,9).
Chronically elevated levels of glucose and fatty acid are thought to contribute to the progression of type 2 diabetes by adversely affecting β-cells and thereby causing a deterioration in insulin secretion (10). In vivo, a reduction in insulin gene expression due to reduced Pdx-1 binding has been observed in rats perifused with glucose and intralipids (11,12). Inaddition, exposure to high levels of glucose and/or free fatty acid has been shown to affect β-cell viability by inducing mitochondrial apoptosis and has been linked to ROS-induced mitochondrial calcium overload and damage (13). Recent studies indicate that nutrient-induced ROS increases subcellular mitochondrial membrane potential (ΔΨmt) heterogeneity and fragmentation of the mitochondrialarchitecture (14,15). These findings suggest that mitochondrial fragmentation-defragmentation might play a role in the effects of noxious stimuli. Although the functional significance of these changes has not been studied in β-cells, studies of mitochondrial morphology in other cells have demonstrated that the ability of mitochondria to form networks influences both ROS and calcium handling (7–9).Previous studies have reported that β-cell mitochondria form less elaborate network structures, compared with COS cells for example, and raise doubts on the existence of mitochondrial networking in these cells. Until now, technologies for examining and quantifying the ability of mitochondria to undergo fusion and fission were unavailable.
In this work, we show that the densely packed appearance ofmitochondria in the β-cell represents the existence of multiple juxtaposed units that do not share continuous matrix lumen but do go through frequent fusion and fission events. We further demonstrate that mitochondrial dynamics are disrupted by exposure to the combination of high fat and glucose, gradually leading to the arrest of fusion activity and complete fragmentation of the mitochondrial...
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