Mitochondrial H2O2 metabolism as early adaptive stress response in heart in Diabetes

RUKAVINA MIKUSIC IA; REY M; ADAN AREAN JS; VANASCO V; ALVAREZ S; VALDEZ LB

Virtual

Congreso; Reunión conjunta de las Sociedades de Biociencias 2021 (virtual).; 2021

SAIC, SAI, AAFE, NANOMED-AR

Background: Insulin signaling is essential for normalmitochondrial function in cardiomyocytes. Hydrogen peroxide (H2O2),the main metabolite effective in redox sensing, signaling and regulation, hasbeen described as an insulinomimetic agent. While physiological H2O2steady-state concentrations ([H2O2]ss) are ~1?10 nM, higher [H2O2]ss lead toadaptive stress responses, and supraphysiological [H2O2]ss(>100 nM) result in oxidative distress. Aim: To study heart mitochondrial H2O2metabolism in an early stage of type 1 diabetes. Methods: Diabetes was induced by Streptozotocin (singledose, 60 mg/kg, ip) in male rats (glycemia at 72 h: 130±5 (C); 415±23 (DM) mg/dl)and animals were sacrificed at day 10. The hearts were removed and mitochondrialfunction, H2O2 metabolism, and lipid peroxidation wereevaluated.Results: State 3 respiration sustained bymalate+glutamate (23%) and complex I activity (17%) were reduced in DM rats. Neitherthe membrane potential nor ATP production were different between groups. MitochondrialH2O2 production was 117% higher in DM rats, and thisincrease was accompanied by the enhancement in the H2O2detoxification enzymes activities and expressions: catalase (200% and 233%) andglutathione peroxidase (26% and 42%), leading to [H2O2]ss~50 nM. Although [GSSG+GSH]mitochondrialwas lower in diabetic rats, there was no difference in GSH/GSSG. Mitochondrial lipidperoxidation, evaluated from 4-HNE expression, was 45% higher in DM than in Canimals.Conclusions: The maintenance of mitochondrial membranepotential, ATP generation and GSH/GSSG suggest the absence of irreversibledamage at this early stage of DM 1. The increase in mitochondrial [H2O2]ssabove the physiological range, but still below 100 nM seems to be part of theadaptive response triggered in cardiomyocytes due to the absence of insulin.