Stress-mediated generation of deleterious ROS in healthy individuals - role of cytochrome c oxidase

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 (ΔΨ_m) low. Above ΔΨ_m 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 ΔΨ_m and ROS formation takes place. The excess production of mitochondrial ROS causes apoptosis or multiple diseases.