Complex I, NO and H2O2 as early markers of heart mitochondrial dysfunction in Type I Diabetes Mellitus model

RUKAVINA MIKUSIC IA; VALDEZ LB; REY M

Mar del Plata

Congreso; Reunion anual de Sociedades de Biociencia: SAIC, SAFE, SAB, SAP, NANOMED-ar, AACyTAL, HCS; 2019

Sociedades de Biociencia: SAIC, SAFE, SAB, SAP, NANOMED-ar, AACyTAL, HCS

INTRODUCTION: Sustained hyperglycemia (25 days) leads to heart mitochondrial dysfunction in the absence of changes in resting cardiac performance (Bombicino et al., 2016, 2017) suggesting that mitochondrial impairment precedes the onset of diabetic cardiac failure. OBJECTIVE: To study the early events that take place in heart mitochondrial dysfunction in a model of Type 1 Diabetes Mellitus (DM), in which hyperglycemia happens without the presence of insulin resistance, obesity, hypercholesterolemia and hypertension. METHODS: Diabetes was induced by a single dose of Streptozoticin (STZ, 60 mg/kg, ip.) in male rats. Glycemia (mg/dl) was determined after 72 h (C: 130±5; DM: 415±23). The animals were sacrificed at day 10 or 14 after injection. O2 consumption, respiratory complexes activities, H2O2 and NO production and NOS expression were determined in heart mitochondrial fraction. PGC-1α expression was measured in heart homogenate. RESULTS: State 3 O2 consumption sustained by malate-glutamate (22%) or by succinate (16%), and complexes I-III (26%), II-III (24%) and IV (20%) activities were lower in DM group, when animals were sacrificed at day 14 (11 days of hyperglycemia). These results were similar to those obtained after 25 days of hyperglycemia. In contrast, when animals were sacrificed at day 10 (7 days of hyperglycemia), only the state 3 O2 consumption sustained by malate-glutamate (22%) and its corresponding respiratory control (39%) were lower in diabetic rats, in accordance with complex I-III activity reduction (19%). Moreover, mitochondrial H2O2 (96%) and NO (25%) production rates and mtNOS expression (79%) were higher in DM group after 7 days of hyperglycemia. While PGC 1α expression increased in diabetic animals (76%) when the hyperglycemia was sustained by 25 days, PGC-1α expression was similar between groups after 10 days of injection, suggesting that mitochondrial biogenesis was not triggered yet. CONCLUSION: Complex I, NO and H2O2 could be considered early markers of cardiac mitochondrial dysfunction. NO and H2O2 appears to be molecules located upstream de novo synthesis of mitochondria, in response to hyperglycemia.