Hyperglycemia-linked metabolites disrupts mitochondrial dynamics and physiology in the central nervous system

VIVIANA GLASER; ALINE PERTILE REMOR; FILIPE JOSE DE MATTOS; LILIANA DEL VALLE SOSA; FLORES-MARTÍN JÉSICA; ZENILDA BOUZON; GENTI DE RAIMONDI SUSANA; ALICIA TORRES; SILVIA OLIVEIRA BRAVO; RODRIGO BRAINY LEAL; ANA DE PAUL; ALEXANDRA LATTINI

Lisboa

Congreso; EBEC 2014; 2014

Chronic hyperglycemia, characteristic of diabetes mellitus (DM), appears to activate pathways implicated in the pathogenesis of DM complications, including methylglyoxal (MG) and advanced glycation end products /AGEs) formation. However, the impact of these compounds on the central nervous system (CNS) is virtually unknown. Here, it was investigated the effect of chronic hyperglycemia, MG and AGEs, on mitochondrial physiology and dynamics in the CNS. Chronic hyperglycemia was induced in Wistar rats by injecting a single dose of streptozotocin (STZ, 55 mg/kg, i.p.) Animals with glycaemia >200 mg/dl were considered hyperglycemnic and were maintained in this condition for 60 days. Control animals received injection of vehicle instead of STZ. It was observed that chronic hyperglycemia changed mitochondrial dynamics o biogenesis in olfactory bulb preparations by increasing the number of mitochondria. In order to better understand the effect of the accumulating metabolites under this hyperglycemic state, we analyzed the individual effect of MG and AGEs treatment induced mitochondrial reorganization, by reducing the size and increasing the number of this organelle in C6 astroglioma cells. In addition, the other hyperglycemic-linked metabolite, MG, provoked increased oxygen consumption (basal respiration and respiring state IV) and reduced 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 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 astrocyte. 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 individual affected by DM.