NO and H2O2 are signalling molecules early involved in cardiac mitochondrial dysfunction observed in Type I Diabetes Mellitus

RUKAVINA MIKUSIC IA; REY M; VALDEZ LB

Aguas de Lindoia

Congreso; 48th Annual meeting of Brazilian Society for Biochemistry and Molecular Biology; 2019

Brazilian Society for Biochemistry and Molecular Biology

INTRODUCTION: NO and H2O2 are considered mitochondrion-cytosol signaling molecules involved in the modulation of redox-sensitive kinase signaling and transcriptional pathways. Mitochondrial productions of these molecules play a critical role in metabolic disorders. Changes in NO steady-state concentration have been associated with mitochondrial biogenesis. OBJECTIVE: The aim is to study the early events that take place in heart mitochondrial dysfunction, including the role of NO and H2O2, in a Type 1 Diabetes Mellitus (DM) model. METHODS: Diabetes was induced by a single dose of Streptozoticin (60 mg/kg, ip.) in male rats. Glycemia was determined after 72 hours (C:130±5 mg/dl; Diabetes:413±26 mg/dl). The animals were sacrificed at day 10 and hearts were removed. O2 consumption, respiratory complexes activities, H2O2 and NO productions, NOS expression and glutathione concentration were determined in mitochondrial fraction. PGC-1expression was measured in heart homogenate. RESULTS: The state 3 O2 consumption sustained by malate-glutamate and its corresponding respiratory control were lower (22%; 39%) in diabetic animals, in accordance with the reduction in complex I-III activity (19%). No differences in O2 uptake sustained by succinate and in the complex II-III or IV activities were observed. The mitochondrial NO production was higher (25%) in diabetic group in agreement with an increase in NOS expression (79%). H2O2 production was also increased (96%). Mitochondrial glutathione concentration was lower in diabetic rats but no differences were observed in GSH/GSSG ratio. PGC-1α expression was similar in both groups, suggesting that mitochondrial biogenesis has not been triggered yet. Linear correlations between the modified mitochondrial parameters and glycemia were observed. CONCLUSIONS: After 7 days of hyperglycemia, heart mitochondrial dysfunction was observed being complex I the only complex modified. There was a closed association between hyperglycemia and mitochondrial dysfunction. Mitochondrial NO and H2O2 could be molecules located upstream other ones that initiate de novo synthesis of mitochondria in response to hyperglycemia.