Abstract
Depletion of mitochondrial endo/exonuclease G-like (EXOG) in cultured neonatal cardiomyocytes stimulates mitochondrial oxygen consumption rate (OCR) and induces hypertrophy via reactive oxygen species (ROS). Here, we show that neurohormonal stress triggers cell death in endo/exonuclease G-like-depleted cells, and this is marked by a decrease in mitochondrial reserve capacity. Neurohormonal stimulation with phenylephrine (PE) did not have an additive effect on the hypertrophic response induced by endo/exonuclease G-like depletion. Interestingly, PE-induced atrial natriuretic peptide (ANP) gene expression was completely abolished in endo/exonuclease G-like-depleted cells, suggesting a reverse signaling function of endo/exonuclease G-like. Endo/exonuclease G-like depletion initially resulted in increased mitochondrial OCR, but this declined upon PE stimulation. In particular, the reserve capacity of the mitochondrial respiratory chain and maximal respiration were the first indicators of perturbations in mitochondrial respiration, and these marked the subsequent decline in mitochondrial function. Although pathological stimulation accelerated these processes, prolonged EXOG depletion also resulted in a decline in mitochondrial function. At early stages of endo/exonuclease G-like depletion, mitochondrial ROS production was increased, but this did not affect mitochondrial DNA (mtDNA) integrity. After prolonged depletion, ROS levels returned to control values, despite hyperpolarization of the mitochondrial membrane. The mitochondrial dysfunction finally resulted in cell death, which appears to be mainly a form of necrosis. In conclusion, endo/exonuclease G-like plays an essential role in cardiomyocyte physiology. Loss of endo/exonuclease G-like results in diminished adaptation to pathological stress. The decline in maximal respiration and reserve capacity is the first sign of mitochondrial dysfunction that determines subsequent cell death.
Highlights
Cardiac hypertrophy is the cellular response to increased ventricular wall stress and can be induced by a variety of pathological stimuli like hypertension, valvular disease and myocardial infarction, and by physiological stimuli including endurance exercise and pregnancy [1,2,3]
We have recently shown that exonuclease G-like (EXOG) depletion stimulates mitochondrial respiration and causes reactive oxygen species (ROS)-mediated cardiomyocyte hypertrophy [14]
We show that EXOG is an important gene in cardiomyocytes and that cell death is enhanced in EXOGdepleted cells treated with the pathological stress factor PE
Summary
Cardiac hypertrophy is the cellular response to increased ventricular wall stress and can be induced by a variety of pathological stimuli like hypertension, valvular disease and myocardial infarction, and by physiological stimuli including endurance exercise and pregnancy [1,2,3]. Hypertrophy is defined by an increase in cardiomyocyte size and is accompanied by enhanced protein synthesis and changes in sarcomere organization [4] This response is initially an adaptive mechanism of the heart to cope with this increased wall stress. Hypertrophy induced by sustained pathological stimulation, like neurohormonal stimulation, is not reversible and may become maladaptive Under these conditions, the initially adaptive response of compensated hypertrophy may advance into decompensated hypertrophy and subsequently result in heart failure [5]. It is more and more recognized that mitochondrial dysfunction is an important event in the development of heart failure [8] This is plausible, as the heart is the most energy-consuming organ in the body and is largely dependent on mitochondrial metabolism to generate energy in the form of ATP to sustain proper cardiac function [9]. The basic aspects of mitochondrial metabolism and energetics, including electron transfer and ATP production, are well established, relatively little is
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