Glaser 2014 Thesis
| Glaser V (2014) Eeitos da hiperglicemia cronica e seus metabolitos, metilglioxal e produtos terminais de glicacao, na fisiologia e dinamica mitochondrial no sistema nervoso central. PhD Thesis 1-117. |
Glaser V (2014) PhD Thesis
Abstract: Diabetes mellitus (DM) is a common metabolic disease characterized by a state of persistent hyperglycemia. The disorder is one of the leading causes of morbidity and mortality worldwide. It is known that chronic hyperglycemic conditions elicit the accumulation of the reactive carbonyl compound methylglyoxal (MG), which has been involved in the formation of advanced glycation end products (AGE). The impact of these compounds on the central nervous system (CNS) is virtually unknown. Therefore, the effect of chronic hyperglycemia and the related metabolites, MG and AGEs, was here investigated on mitochondrial physiology and dynamics in the CNS. For this, chronic hyperglycemia was induced in Wistar rats by injecting a single dose of streptozotocin (STZ, 55 mg/kg, intraperitoneally). Animals with glycaemia > 200mg/dL were considered hyperglycemic. Some animals were maintained in this condition for 60 days (STZ group), and others received daily injections of insulin (1.5 IU, twice a day; STZ+INS group) in order to normalize blood glucose levels. Controls animals received a single injection of vehicle instead of STZ. It was observed that chronic hyperglycemia did not change mitochondrial dynamics or biogenesis in cerebral cortex of rats. However, insulin administration elicited increased Tfam expression and mitochondrial size. In contrast, a marked increase in mitochondrial number was observed in olfactory bulb preparations from STZ-treated animals. In order to better understand the effect of the accumulating metabolites under this hyperglycemic state, we then analyzed the individual effect of MG and AGEs on mitochondria dynamic or physiology in cultured astrocytes. It was observed that AGEs treatment induced mitochondrial reorganization, by reducing the size and increasing the number of this organelle in C6 astroglioma cells. However, this phenomenon that points to increased mitochondria fission, was accompanied by unchanged content of Mfn2 (fusion protein) and Drp1 (fission protein) proteins. In addition, the other hyperglycemic-linked metabolite, MG, provoked increased oxygen consumption (basal respiration and respiring state IV) and reduced the mitochondrial respiratory control, indicating MG-induced uncoupling of mitochondria. In agreement, AGEs provoked reduced mitochondrial membrane potential on rat primary cortical astrocyte cell culture, suggesting that the altered mitochondrial dynamics is directly related to the MG uncoupling properties. Furthermore, the increased content of uncoupled mitochondria did not stimulate autophagy, indicating that dysfunctional reactive oxygen species-producing organelles are being accumulated in the nerve cell. In conclusion, chronic hyperglycemia and hyperglycemia-linked metabolites (MG and AGEs) disrupts mitochondrial dynamics and physiology in nerve cells. The phenomenon might induce cell death, and therefore, a higher predisposition for neurodegenerative disorders development in patients with DM. • Keywords: Hyperglycemia, Methylglyoxal, Advanced glycation end products, Mitochondria physiology, Mitochondrial dynamics, Mitophagy, Neurotoxicity
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