Abstract
Psychosocial stress is known to cause an increased incidence of coronary heart disease. In addition, multiple other diseases like cancer and diabetes mellitus have been related to stress and are mainly based on excessive formation of reactive oxygen species (ROS) in mitochondria. The molecular interactions between stress and ROS, however, are still unknown. Here we describe the missing molecular link between stress and an increased cellular ROS, based on the regulation of cytochrome c oxidase (COX). In normal healthy cells, the “allosteric ATP inhibition of COX” decreases the oxygen uptake of mitochondria at high ATP/ADP ratios and keeps the mitochondrial membrane potential (ΔΨm) low. Above ΔΨm values of 140 mV, the production of ROS in mitochondria increases exponentially. Stress signals like hypoxia, stress hormones, and high glutamate or glucose in neurons increase the cytosolic Ca2+ concentration which activates a mitochondrial phosphatase that dephosphorylates COX. This dephosphorylated COX exhibits no allosteric ATP inhibition; consequently, an increase of ΔΨm and ROS formation takes place. The excess production of mitochondrial ROS causes apoptosis or multiple diseases.
Highlights
Psychosocial stress is known to cause cardiovascular diseases including increased heart rate, high blood pressure, energy mobilization, decreased insulin sensitivity, and endothelial dysfunction [1]
This mechanism includes a stress-induced increase of cytosolic calcium, J Mol Med (2020) 98:651–657 followed by dephosphorylation of cytochrome c oxidase (COX), loss of “allosteric ATP inhibition of COX,” increase of mitochondrial membrane potential ΔΨm, and the formation of reactive oxygen species (ROS)
We conclude that the health in all higher organisms is based on the maintenance of a low mitochondrial membrane potential ΔΨm via the “allosteric ATP inhibition of COX,” which prevents the formation of high and deleterious amounts of ROS
Summary
Psychosocial stress is known to cause cardiovascular diseases including increased heart rate, high blood pressure, energy mobilization, decreased insulin sensitivity, and endothelial dysfunction [1]. The above-reviewed data explains how stress could induce excessive production of ROS in mitochondria by switching off the allosteric ATP inhibition of COX, which under relaxed conditions, keeps ΔΨm From these results, we conclude that the health in all higher organisms is based on the maintenance of a low mitochondrial membrane potential ΔΨm via the “allosteric ATP inhibition of COX,” which prevents the formation of high and deleterious amounts of ROS. In living animals of a rat stroke model with a longitudinal analysis of brain injury using magnetic resonance imaging, a sustained reduction in infarct volume following ischemic stroke was found after exposure to near-infrared light [94] These results with living rats coincide with the conclusion derived from results on the allosteric ATP inhibition of COX that attenuation of COX activity prevents the increase of ΔΨm to values resulting in deleterious mitochondrial ROS production. Another way to decrease ΔΨm and ROS generation in mitochondria is by using uncoupler of oxidative phosphorylation, which induces a backflow of translocated protons at the inner mitochondrial membrane [95]
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