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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM087483-04S1
Application #
8575639
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Deatherage, James F
Project Start
2010-01-01
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$51,344
Indirect Cost
$17,895
Name
University of Rochester
Department
Anesthesiology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Queliconi, Bruno B; Kowaltowski, Alicia J; Nehrke, Keith (2014) An anoxia-starvation model for ischemia/reperfusion in C. elegans. J Vis Exp :
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
Wojtovich, Andrew P; Urciuoli, William R; Chatterjee, Shampa et al. (2013) Kir6.2 is not the mitochondrial KATP channel but is required for cardioprotection by ischemic preconditioning. Am J Physiol Heart Circ Physiol 304:H1439-45
Queliconi, Bruno B; Marazzi, Thire B M; Vaz, Sandra M et al. (2013) Bicarbonate modulates oxidative and functional damage in ischemia-reperfusion. Free Radic Biol Med 55:46-53
Wojtovich, Andrew P; Smith, C Owen; Haynes, Cole M et al. (2013) Physiological consequences of complex II inhibition for aging, disease, and the mKATP channel. Biochim Biophys Acta 1827:598-611
Wojtovich, Andrew P; DiStefano, Peter; Sherman, Teresa et al. (2012) Mitochondrial ATP-sensitive potassium channel activity and hypoxic preconditioning are independent of an inwardly rectifying potassium channel subunit in Caenorhabditis elegans. FEBS Lett 586:428-34
Wojtovich, Andrew P; Nadtochiy, Sergiy M; Brookes, Paul S et al. (2012) Ischemic preconditioning: the role of mitochondria and aging. Exp Gerontol 47:1-7
Wojtovich, Andrew P; Sherman, Teresa A; Nadtochiy, Sergiy M et al. (2011) SLO-2 is cytoprotective and contributes to mitochondrial potassium transport. PLoS One 6:e28287
Queliconi, Bruno B; Wojtovich, Andrew P; Nadtochiy, Sergiy M et al. (2011) Redox regulation of the mitochondrial K(ATP) channel in cardioprotection. Biochim Biophys Acta 1813:1309-15

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