The Saccharomyces cerevisiae mitochondrial unselective channel behaves as a physiological uncoupling system regulated by Ca^sup 2+^, Mg^sup 2+^, phosphate and ATP

It is proposed that the Saccharomyces cerevisiae the Mitochondrial Unselective Channel (^sub Sc^MUC) is tightly regulated constituting a physiological uncoupling system that prevents overproduction of reactive oxygen species (ROS). Mg^sup 2+^, Ca^sup 2+^ or phosphate (Pi) close ^sub Sc^MUC, while ATP or a high rate of oxygen consumption open it. We assessed ^sub Sc^MUC activity by measuring in isolated mitochondria the respiratory control, transmembrane potential (ΔΨ), swelling and production of ROS. At increasing [Pi], less [Ca^sup 2+^] and/or [Mg^sup 2+^] were needed to close ^sub Sc^MUC or increase ATP synthesis. The Ca^sup 2+^-mediated closure of ^sub Sc^MUC was prevented by high [ATP] while the Mg^sup 2+^ or Pi effect was not. When Ca^sup 2+^ and Mg^sup 2+^ were alternatively added or chelated, ^sub Sc^MUC opened and closed reversibly. Different effects of Ca^sup 2+^ vs Mg^sup 2+^ effects were probably due to mitochondrial Mg^sup 2+^ uptake. Our results suggest that ^sub Sc^MUC activity is dynamically controlled by both the ATP/Pi ratio and divalent cation fluctuations. It is proposed that the reversible opening/closing of ^sub Sc^MUC leads to physiological uncoupling and a consequent decrease in ROS production.