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Title: Oxidative stress and susceptibility to mitochondrial permeability transition precedes the onset of diabetes in autoimmune non-obese diabetic mice
Author: Malaguti, C.; La Guardia, P. G.; Leite, A. C. R.; Oliveira, D. N.; De Lima Zollner, R. L.; Catharino, R. R.; Vercesi, A. E.; Oliveira, H. C. F.
Year: 2014
Is part of: FREE RADICAL RESEARCH, v. 48, p. 1494 - 1504
DOI: https://doi.org/10.3109/10715762.2014.966706

Citation: Malaguti, C.; La Guardia, P. G.; Leite, A. C. R.; Oliveira, D. N.; De Lima Zollner, R. L.; Catharino, R. R.; Vercesi, A. E.; Oliveira, H. C. F.; Oxidative stress and susceptibility to mitochondrial permeability transition precedes the onset of diabetes in autoimmune non-obese diabetic mice. FREE RADICAL RESEARCH, v.48, p. 1494-1504, 2014

Abstract: Beta cell destruction in type 1 diabetes (TID) is associated with cellular oxidative stress and mitochondrial pathway of cell death. The aim of this study was to determine whether oxidative stress and mitochondrial dysfunction are present in T1D model (non-obese diabetic mouse, NOD) and if they are related to the stages of disease development. NOD mice were studied at three stages: non-diabetic, pre-diabetic, and diabetic and compared with age-matched Balb/c mice. Mitochondria respiration rates measured at phosphorylating and resting states in liver and soleus biopsies and in isolated liver mitochondria were similar in NOD and Balb/c mice at the three disease stages. However, NOD liver mitochondria were more susceptible to calcium-induced mitochondrial permeability transition as determined by cyclosporine-A-sensitive swelling and by decreased calcium retention capacity in all three stages of diabetes development. Mitochondria H2O2 production rate was higher in non-diabetic, but unaltered in pre-diabetic and diabetic NOD mice. The global cell reactive oxygen species (ROS), but not specific mitochondria ROS production, was significantly increased in NOD lymphomononuclear and stem cells in all disease stages. In addition, marked elevated rates of 2',7' -dichlorodihydrofl uorescein (H2DCF) oxidation were observed in pancreatic islets from non-diabetic NOD mice. Using matrix-assisted laser desorption/ ionization (MALDI) mass spectrometry (MS) and lipidomic approach, we identified oxidized lipid markers in NOD liver mitochondria for each disease stage, most of them being derivatives of diacylglycerols and phospholipids. These results suggest that the cellular oxidative stress precedes the establishment of diabetes and may be the cause of mitochondrial dysfunction that is involved in beta cell death.

Keywords: lymphomononuclear cells; mitochondria; pancreatic islet; reactive oxigen species; type I diabetes;
Subjects: CIENCIAS_BIOLOGICAS; Metabolismo e Bioenergética; CIENCIAS_BIOLOGICAS; Bioquímica; Metabolismo e Bioenergética; Bioenergética Mitocondrial;


Funding: This study was supported by grants obtained by HCFO and AEV from the Brazilian agencies: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP # 2011/50400-0 and 2011/51349-8) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). CM, PGG, ACRL, and DNO were supported by Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) fellowships.
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