Nutrient-induced ?-cell dysfunction and death are thought to play a central role in the development of diabetes. Pathogenic and defense mechanisms that respond to a high fat and carbohydrate environment (HFC) may provide valuable therapeutic targets. Research supported by this grant established mitochondrial fusion-fission and autophagy as linked events that form the mitochondrial life cycle. Furthermore we determined that HFC arrests the mitochondrial life cycle by preventing mitochondrial fusion, leading to the complete fragmentation of the mitochondrial network and stimulation of mitochondrial turnover by mitophagy. Preliminary in vivo and in vitro data indicate that fragmentation is mediated by HFC-induced degradation of the mitochondrial fusion protein, Mfn2. Remarkably, we find that in vivo deletion or in vitro knockdown of Mfn2 leads to increased uncoupling, decreased ROS and protection of ?-cell viability. These beneficial effects come at the expense of deregulated insulin secretion, manifested by increased basal secretion, decreased 1st phase, increased 2nd phase and a blunted oscillatory pattern. We hypothesize that HFC-induced degradation of islet Mfn2 and the ensuing network fragmentation serves to protect ?-cell viability as a compensatory mechanism while at the same time deregulating insulin secretion. We will address this hypothesis through the following Aims:
Aim1 will determine the role of Mfn2 turnover in the prevention of ?-cell loss and will evaluate the potential use of Mfn2 downregulation as a therapeutic target in diabetic models.
Aim2 will determine the contribution of Mfn2 turnover to HFC-induced deregulation of insulin secretion and the mechanism by which Mfn2 modulates secretion.
Aim3 will investigate the mechanism by which Mfn2 turnover is controlled in the ?-cell. Our preliminary studies have identified a novel mechanism for the stimulation of Mfn2 turnover which we have been able to activate pharmacologically. We will evaluate this novel therapeutic target as a mechanism to induce adaptation. Revealing the pathways that mediate the dual effects of Mfn2 turnover will allow for the devise of interventions that will maintain the beneficial effect while suppressing the detrimental.
The ability of the majority of the population to adapt to the obese state and not develop impaired glucose tolerance suggests the existence of compensatory mechanisms. This proposal stems from our recent identification of a molecular event that results in the protection of the insulin producing cells and allows for enhanced insulin secretion. Experiments proposed in this study will help decipher the beneficial from the detrimental processes within the adaptive response, thereby allowing for the identification of therapeutic targets for the prevention of diabetes.
|Cerqueira, Fernanda M; Chausse, Bruno; Baranovski, Boris M et al. (2016) Diluted serum from calorie-restricted animals promotes mitochondrial Î²-cell adaptations and protect against glucolipotoxicity. FEBS J 283:822-33|
|Forni, Maria Fernanda; Peloggia, Julia; Trudeau, Kyle et al. (2016) Murine Mesenchymal Stem Cell Commitment to Differentiation Is Regulated by Mitochondrial Dynamics. Stem Cells 34:743-55|
|Trudeau, Kyle M; Colby, Aaron H; Zeng, Jialiu et al. (2016) Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity. J Cell Biol 214:25-34|
|Schwartz, Stanley S; Epstein, Solomon; Corkey, Barbara E et al. (2016) The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the Î²-Cell-Centric Classification Schema. Diabetes Care 39:179-86|
|Berdan, Charles A; Erion, Karel A; Burritt, Nathan E et al. (2016) Inhibition of Monoacylglycerol Lipase Activity Decreases Glucose-Stimulated Insulin Secretion in INS-1 (832/13) Cells and Rat Islets. PLoS One 11:e0149008|
|Qiu, Wei; Liesa, Marc; Carpenter, Elizabeth P et al. (2015) ATP Binding and Hydrolysis Properties of ABCB10 and Their Regulation by Glutathione. PLoS One 10:e0129772|
|Shirihai, Orian S; Song, Moshi; Dorn 2nd, Gerald W (2015) How mitochondrial dynamism orchestrates mitophagy. Circ Res 116:1835-49|
|Las, Guy; Shirihai, Orian S (2014) Miro1: new wheels for transferring mitochondria. EMBO J 33:939-41|
|Wikstrom, Jakob D; Mahdaviani, Kiana; Liesa, Marc et al. (2014) Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure. EMBO J 33:418-36|
|Patel, Pinkesh K; Shirihai, Orian; Huang, Kerwyn Casey (2013) Optimal dynamics for quality control in spatially distributed mitochondrial networks. PLoS Comput Biol 9:e1003108|
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