The overall goal of our research program is to elucidate endogenous and other mechanisms of protection against ischemia-reperfusion (IR) injury, and to exploit this knowledge to develop new therapies for IR disease conditions such as heart attack and stroke. Many cardioprotective strategies appear to converge on mitochondrial potassium channels as necessary and sufficient effectors of protective signaling. However, the identity and regulation of these channels remains controversial. Our published research to date, and exciting preliminary data contained herein, have directed our focus to a novel mitochondrial K+ channel that is required for protection and has not previously been implicated in protective signaling. Notably, absence of this channel appears to yield a metabolic phenotype. We have also identified a novel class of endogenous channel modulators. In this proposal, Aim 1 will characterize the channel and its role in cardioprotection, Aim 2 will investigate links between the channel and cardiac metabolism, and Aim 3 will study its regulation by endogenous signals. We will use a variety of state-of-the -art techniques, including patch-clamp of mitoplasts (isolated mitochondrial inner membranes), and Seahorse XF methodology to assess cardiomyocyte bioenergetics. This dual-PI proposal draws on the expertise of both investigators (Brookes - mitochondrial biology, metabolic screening, cardiac patho-physiology;Nehrke - ion channels, mouse genetics, mitochondrial physiology). Our productive track-record (8 original research articles and 3 reviews funded by this project in 3 years) imparts a high probability that the completion of these 3 aims will yield critical information about this channel, which is a novel potential drug target for cardioprotection.

Public Health Relevance

Heart attack is responsible for >220,000 deaths per year in the USA, and a further ~380,000 patients undergo cardiac surgery every year. Hence there is a drastic need for therapies to avoid myocardial injury. We have identified a novel molecular target (a potassium channel in mitochondria) whose activity is both necessary and sufficient for protection from ischemia. The proposed project will investigate the properties of this channel and its role in cardio protection.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-M (02))
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Nie, Zhongzhen
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University of Rochester
Schools of Dentistry
United States
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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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