Dr. Ryan J. Mailloux - February 17

Control of mitochondrial bioenergetics by redox signaling; importance of S-glutathionylation reactions in cardiac metabolism and physiology

Mitochondria are energy-transforming organelles that convert energy stored in carbon bonds of nutrients into ATP. Coupling exergonic electron transfer reactions to the genesis ATP can also lead the production of reactive oxygen species (ROS) which serve as important signaling molecules at low concentrations but can damage cells if levels are sufficiently high. Thus, production of ATP and ROS are intimately linked to nutrient oxidation and the respiratory chain and the genesis of one or the other inherently depends on the metabolic state and redox poise of mitochondria. Control over electron transfer reactions is paramount in mitochondria since a tissue’s energy demands are constantly changing. Also, tight control over ROS production must also be exercised so a cell can benefit from its signaling properties whilst avoiding its toxicity. Redox signaling has recently been shown to play a crucial role in modulating mitochondrial function since it provides a direct link between ROS production and control of enzyme catalysis through oxidation of protein cysteine thiols. In particular, conjugation of glutathione to protein cysteine thiols in response to redox environmental fluctuations, termed S-glutathionyation, has shown to be important in controlling mitochondrial bioenergetics. Here, the importance of reversible S-glutathionylation in the control of oxidative phosphorylation and ROS production in cardiac mitochondria is discussed in detail. Focus will be given to glutaredoxin-2 (Grx2), a thiol oxidoreductase, and its importance in driving reversible S-glutathionylation of Complex I and other mitochondrial proteins and the impact these reactions have on ATP production. Finally, the impact of loss of a functional Grx2 enzyme and the development of cardiac disease will also be discussed alongside the potential for developing mitochondria-targeted pharmaceuticals that can restore the mitochondrial redox environment and S-glutathionylated proteome



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