Controlling mitochondrial bioenergetics with protein S-glutathionylation redox switches

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Mitochondria are required to furnish mammalian cells with ATP, a usable form of energy that performs useful “work” in a cell. ATP is generated by oxidative phosphorylation (OXPHOS) which couples the energy released from nutrient metabolism to the phosphorylation of ADP. Akin to an electrical wire, electrons liberated from nutrients are ferried through electron conducting protein complexes to molecular oxygen (O2) at the end of the chain. Electron movement to O2 is a “favorable process” which means that electron movement releases energy that can be trapped for the production of ATP. Unfortunately OXPHOS is not a perfect process and sometimes electrons can “leak” out of the chain and prematurely interact with O2 generating reactive oxygen species (ROS). ROS are dangerous at high quantities but low amounts are required to coordinate mitochondrial functions with changes in cell physiology. Indeed, ROS are required to drive basic cellular functions ranging from cell proliferation to wound healing and heart function. What is truly surprising is that despite 50 years of research we only have a rudimentary understanding of how mitochondria control ROS formation. Given its dichotomy, it would seem quite important to decipher how mitochondria modulate how much ROS is produced. One way to control ROS is with endogenous antioxidants like glutathione (GSH) which is found at high levels in mitochondria. Another way is with redox switches which can control the entry and exit of electrons from sites of ROS production. One switch that has gained a lot of attention is protein S-glutathionylation (PGlu) which involves the physical attachment and removal of GSH from enzymes. PGlu reactions are attractive switches for controlling mitochondrial OXPHOS and ROS production since the switches themselves are directly influenced by how much GSH is interacting with ROS. My long term research focus is to provide the first in depth assessment of the function of PGlu in controlling mitochondrial bioenergetics and ROS production. The overall goal is to enhance our understanding of how this redox switch controls the production of an important signaling molecule, ROS. This includes identifying which enzymes are controlled by PGlu and the impact it has on OXPHOS and ROS formation at these specific sites. This would be the first research program in Canada that dissects the function of redox switches in controlling mitochondrial metabolism and ROS formation. It also broaches for the first time the function of redox switches in controlling the assembly of mitochondrial proteins involved in ROS formation. The redox biology field is a new field filled with exciting and dynamic research and it is thus anticipated that the novelty of this research program will significantly advance our understanding of the role of redox switches in controlling mitochondria and ROS signaling.