Cysteine Switches and the Regulation of Mitochondrial Bioenergetics and ROS Production

Abstract

Mitochondria are dynamic organelles that perform a number of interconnected tasks that are elegantly intertwined with the regulation of cell functions. This includes the provision of ATP, reactive oxygen species (ROS), and building blocks for the biosynthesis of macromolecules while also serving as signaling platforms for the cell. Although the functions executed by mitochondria are complex, at its core these roles are, to a certain degree, fulfilled by electron transfer reactions and the establishment of a protonmotive force (PMF). Indeed, mitochondria are energy conserving organelles that extract electrons from nutrients to establish a PMF, which is then used to drive ATP and NADPH production, solute import, and many other functions including the propagation of cell signals. These same electrons extracted from nutrients are also used to produce ROS, pro-oxidants that can have potentially damaging effects at high levels, but also serve as secondary messengers at low amounts. Mitochondria are also enriched with antioxidant defenses, which are required to buffer cellular ROS. These same redox buffering networks also fulfill another important role; regulation of proteins through the reversible oxidation of cysteine switches. The modification of cysteine switches with the antioxidant glutathione, a process called protein S-glutathionylation, has been found to play an integral role in controlling various mitochondrial functions. In addition, recent findings have demonstrated that disrupting mitochondrial protein S-glutathionylation reactions can have some dire pathological consequences. Accordingly, this chapter focuses on the role of mitochondrial cysteine switches in the modulation of different physiological functions and how defects in these pathways contribute to the development of disease.