Acute kidney injury resulting from ischemia reperfusion or toxin induced damage is correlated with mitochondrial dysfunction and increased ROS levels. The damaging effects of ROS on DNA, protein and lipids can be ameliorated by cellular antioxidants that detoxify the ROS. I have identified a novel mechanism of cellular detoxification in the mitochondria by a predicted pseudokinase, Selenoprotein O (SelO). Preliminary studies using E. coli and S. cerevisiae demonstrates that SelO catalyzes the transfer of AMP from ATP to multiple substrates involved in redox homeostasis to dampen oxidative damage and prevent cell death. Due to the phyletic spread and conservation from bacteria to humans, we postulate that SelO will play a role in oxidative stress response in mammalian systems that are heavily dependent on the mitochondria, such as the kidney. We will test this hypothesis by identifying the molecular targets and pathways mediated by SelO, and characterizing the functional importance of SelO in the rodent cisplatin-induced acute kidney injury model. A deep understanding and technical expertise in the fields of oxidative stress and nephrology are essential to the successful completion of this proposal. This career development award will allow me to strengthen my scientific skill set by training in kidney isolation, staining and phenotypic characterization in combination with biochemical assays to evaluate mitochondrial health. These studies will define a novel paradigm of signaling in the mitochondria, which can be usurped to identify therapeutic targets to prevent oxidative damage in a plethora of pathologies including acute kidney injury.
Selenoprotein O (SelO) catalyzes a previously undocumented post translational modification in the mitochondria to target multiple proteins involved in the production and clearance of reactive oxygen species. These results define a new mitochondrial signaling cascade that regulates redox homeostasis to protect the cells from oxidative damage. The goal of this proposal is to define the molecular and cellular mechanisms of SelO-mediated oxidative stress response in the kidney.
