Acute myocardial infarction is a leading cause of death throughout the world, while stroke is the third leading cause of death in the United States. Ischemia-reperfusion injury associated with these conditions can lead to permanent tissue damage or neurologic deficits. It is well recognized that non-lethal exposure to ischemia for short periods of time however, elicits a proadaptive response that protects cells from subsequent ischemic injury in a process referred to as preconditioning. Mitochondria are central to the pathogenesis of ischemia- perfusion injury and are believed to be a major target for preconditioning. In particular, ion channels in the inner mitochondrial membrane that transport potassium (KATP and KCa channels) are believed to attenuate the mitochondrial cell death response following preconditioning. The molecular identity of these channels is controversial. The major goal of this proposal is to unambiguously identify the mitochondrial KATP and KCa channels, and a second goal is to identify signaling processes that regulate channel activity in the mitochondria in response to preconditioning. The experiments designed to meet these goals will be carried out in the nematode C. elegans. It has recently been shown that preconditioning can protect this genetic model organism from hypoxic injury and death. Moreover, we have found that C. elegans express functional KATP and KCa channels in their mitochondria. We propose to combine the strengths of two investigators, one with extensive experience in mitochondrial bioenergetics and cardiovascular physiology, and the other in nematode ion channel physiology, to test the hypothesis that KATP and KCa channel regulation is an evolutionarily conserved mechanism that contributes to preconditioning in C. elegans. We will utilize the vast array of genetic resources available in C. elegans to screen strains containing mutations in candidate genes for channel activity in purified mitochondria, for channel regulation via conserved signaling pathways, and for their ability to be preconditioned. The results from these experiments will improve our ability to develop protective therapeutics targeted at channels or upstream regulators and designed to mimic the effects of preconditioning in mammals.
Reduced oxygen availability causes cellular damage and death, particularly in neurons (via stroke) or cardiac myocytes (via heart attack). However, brief sub-lethal exposure to low oxygen can lead to proadaptive mechanisms that protect against subsequent decreases in oxygen. This process is called """"""""preconditioning"""""""" and acts as an evolutionarily conserved early warning system in all cell types and organisms examined so far. We propose to determine the molecular identity of membrane ion transporters that have been implicated in this proadaptive conditioning via their function in the mitochondria and to study their regulation using the genetic model organism C. elegans. The identification of these molecules will help in the development of new therapies for heart attack and stroke.
|Smith, Charles O; Wang, Yves T; Nadtochiy, Sergiy M et al. (2018) Cardiac metabolic effects of KNa1.2 channel deletion and evidence for its mitochondrial localization. FASEB J :fj201800139R|
|Smith, Charles Owen; Nehrke, Keith; Brookes, Paul S (2017) The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection. Biochem J 474:2067-2094|
|Wojtovich, Andrew P; Smith, C Owen; Urciuoli, William R et al. (2016) Cardiac Slo2.1 Is Required for Volatile Anesthetic Stimulation of K+ Transport and Anesthetic Preconditioning. Anesthesiology 124:1065-76|
|Wojtovich, Andrew P; Wei, Alicia Y; Sherman, Teresa A et al. (2016) Chromophore-Assisted Light Inactivation of Mitochondrial Electron Transport Chain Complex II in Caenorhabditis elegans. Sci Rep 6:29695|
|Nehrke, Keith (2016) H(OH), H(OH), H(OH): a holiday perspective. Focus on ""Mouse Slc4a11 expressed in Xenopus oocytes is an ideally selective H+/OH- conductance pathway that is stimulated by rises in intracellular and extracellular pH"". Am J Physiol Cell Physiol 311:C942-C944|
|Wojtovich, Andrew P; Foster, Thomas H (2014) Optogenetic control of ROS production. Redox Biol 2:368-76|
|Raphemot, Rene; Swale, Daniel R; Dadi, Prasanna K et al. (2014) Direct activation of ?-cell KATP channels with a novel xanthine derivative. Mol Pharmacol 85:858-65|
|Queliconi, Bruno B; Kowaltowski, Alicia J; Nehrke, Keith (2014) An anoxia-starvation model for ischemia/reperfusion in C. elegans. J Vis Exp :|
|Nehrke, Keith (2014) Membrane ion transport in non-excitable tissues. WormBook :1-22|
|Wojtovich, Andrew P; Nadtochiy, Sergiy M; Urciuoli, William R et al. (2013) A non-cardiomyocyte autonomous mechanism of cardioprotection involving the SLO1 BK channel. PeerJ 1:e48|
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