In EXOG‐depleted cardiomyocytes cell death is marked by a decreased mitochondrial reserve capacity of the electron transport chain

• Published in: Inside the cell 2016-04, Vol.1 (2), p.134-143
• Main Authors: Tigchelaar, Wardit, De Jong, Anne Margreet, Gilst, Wiek H., De Boer, Rudolf A., Silljé, Herman H. W.
• Format: Article
• Language: English
• Subjects: cardiomyocyte; cell death; EXOG; hypertrophy; mitochondria
• ISSN: 2375-2920; 2375-2920
• DOI: 10.1002/icl3.1047

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. Mitochondrial Endonuclease G‐like‐1 (EXOG) modulates mitochondrial respiration and hypertrophy in cardiomyocytes. Here we show that pathological stimulation of EXOG depleted cardiomyocytes results in a diminished mitochondrial reserve capacity, which marks subsequent cell death. EXOG is therefore essential in pathological stress adaptation and to maintain cell viability.