Wai-Meng Kwok, PhD
Director of Basic Science Research, Professor
Mitochondrial ion channels
Post-translational modifications of mitochondrial ion channels in response to stressMitochondria are involved in a myriad of complex signaling cascades regulating cell death vs. survival. Importantly, mitochondrial dysfunction and the resulting oxidative and nitrosative stress via reactive oxygen and nitrogen species (ROS, RNS) are central in the etiology of numerous human maladies, including neurodegenerative and cardiac diseases. One of the vital proteins that regulate mitochondrial function/dysfunction is the voltage dependent anion channel 1 (VDAC1), the most abundant protein on the outer mitochondrial membrane (OMM) and a major regulatory gateway in and out of the organelle. Because of its pivotal roles in the exchange of metabolites and ions, and mediating cell death, VDAC1 is known as the gatekeeper for mitochondrial function. Post-translational modifications (PTMs, for example phosphorylation, nitrosylation, and nitration) of VDAC1 have been implicated in a number of diseases, but the consequences of PTMs on VDAC1 function and subsequently on mitochondrial and cellular functions are not well understood. Thus, our overall goal is to unravel the functional significance and consequence of PTMs on VDAC1. We employ a highly orchestrated approach that includes electrophysiology, molecular biology, mitochondrial biology, proteomics and transgenic animal models to investigate how functional and structural changes in VDAC1 tip the balance between cell survival and cell death. Our long term goal is to delineate how PTMs of VDAC1 contribute to the pathogenesis of ischemic heart disease as well as other mitochondrial-related diseases, such as Huntington’s and Alzheimer’s.
Sarcolemmal ion channels
Volatile anesthetics and ion channelsSarcolemmal ion channels underlie the cardiac action potential profile. Any perturbation in ion channel function can potentially be arrhythmogenic. Volatile anesthetics have been documented to impact cardiac rhythm. To investigate the underlying molecular mechanisms, we have published extensively on the impact of these agents on the cardiac sodium, calcium and potassium channel function and reported on their conformational state-, frequency-, and voltage-dependent effects. These studies revealed the complex interaction of volatile anesthetics with several types of cardiac ion channels. Some of our key findings include 1) protein kinase C modulation of the sarcolemmal KATP channel in volatile anesthetic-induced cardioprotection, 2) identification of the molecular mechanism underlying the effects of anesthetics on the cardiac IKs channel, a protein associated with the long QT syndrome, and 3) changes in the biophysical characteristics of the L-type calcium channel triggered by anesthetic-induced cardioprotection.
Modeling cardiac arrhythmias in a dishBased on our expertise in cardiac electrophysiology, we have extended our research boundaries beyond anesthetic modulation of cardiac ion channels to modeling arrhythmias at the cellular level. We are currently collaborating with stem cell researchers in the Cardiovascular Center at MCW to develop a cellular model of cardiac arrhythmias. Specifically, our objective is to utilize patient-specific induced pluripotent stem cell (iPSC) derived cardiomyocytes to establish a clinically relevant model of atrial fibrillation (AF) that exhibits arrhythmogenic characteristics. AF is the most common type of cardiac arrhythmias that is clinically observed, and is associated with a wide range of potential complications, including stroke and death. Although animal models of AF have been developed, there is currently no human-based cellular model. Such a model will greatly enhance our understanding of the molecular mechanism underlying AF and could potentially lead to a more efficacious therapeutic management of AF that remains elusive. Our long term goals are to establish a unique platform for delineating the molecular mechanism underlying AF, and for testing various therapeutic strategies in the management of patient-specific AF.
(Mishra J, Davani AJ, Natarajan GK, Kwok WM, Stowe DF, Camara AKS.) Cells. 2019 09 07;8(9) PMID: 31500337 PMCID: PMC6770067 SCOPUS ID: 2-s2.0-85082240408 09/11/2019
(Wan TC, Tampo A, Kwok WM, Auchampach JA.) Biochem Pharmacol. 2019 05;163:21-31 PMID: 30710517 PMCID: PMC6470012 SCOPUS ID: 2-s2.0-85061006338 02/03/2019
(Yang M, Xu Y, Heisner JS, Sun J, Stowe DF, Kwok WM, Camara AKS.) Mitochondrion. 2019 05;46:380-392 PMID: 30391711 PMCID: PMC6487210 SCOPUS ID: 2-s2.0-85056228802 11/06/2018
(Haumann J, Camara AKS, Gadicherla AK, Navarro CD, Boelens AD, Blomeyer CA, Dash RK, Boswell MR, Kwok WM, Stowe DF.) Front Physiol. 2018;9:1914 PMID: 30804812 PMCID: PMC6378946 02/26/2019
(Yang M, Camara AKS, Aldakkak M, Kwok WM, Stowe DF.) Biochim Biophys Acta Bioenerg. 2017 Jun;1858(6):442-458 PMID: 28342809 PMCID: PMC5749404 SCOPUS ID: 2-s2.0-85017126810 03/28/2017
(Gadicherla AK, Wang N, Bulic M, Agullo-Pascual E, Lissoni A, De Smet M, Delmar M, Bultynck G, Krysko DV, Camara A, Schlüter KD, Schulz R, Kwok WM, Leybaert L.) Basic Res Cardiol. 2017 05;112(3):27 PMID: 28364353 04/02/2017
(Camara AKS, Zhou Y, Wen PC, Tajkhorshid E, Kwok WM.) Front Physiol. 2017;8:460 PMID: 28713289 PMCID: PMC5491678 07/18/2017
(Runge CL, Indap A, Zhou Y, Kent JW Jr, King E, Erbe CB, Cole R, Littrell J, Merath K, James R, Rüschendorf F, Kerschner JE, Marth G, Hübner N, Göring HH, Friedland DR, Kwok WM, Olivier M.) JAMA Otolaryngol Head Neck Surg. 2016 09 01;142(9):866-72 PMID: 27311106 PMCID: PMC5025373 SCOPUS ID: 2-s2.0-84997646398 06/17/2016
(Mitzelfelt KA, Limphong P, Choi MJ, Kondrat FD, Lai S, Kolander KD, Kwok WM, Dai Q, Grzybowski MN, Zhang H, Taylor GM, Lui Q, Thao MT, Hudson JA, Barresi R, Bushby K, Jungbluth H, Wraige E, Geurts AM, Benesch JL, Riedel M, Christians ES, Minella AC, Benjamin IJ.) J Biol Chem. 2016 07 15;291(29):14939-53 PMID: 27226619 PMCID: PMC4946913 SCOPUS ID: 2-s2.0-84978431927 05/27/2016
(Raphael R, Purushotham D, Gastonguay C, Chesnik MA, Kwok WM, Wu HE, Shah SJ, Mirza SP, Strande JL.) J Transl Med. 2016 Jan 20;14:18 PMID: 26792056 PMCID: PMC4719542 SCOPUS ID: 2-s2.0-84955276098 01/23/2016
(Mikuni I, Torres CG, Bakshi T, Tampo A, Carlson BE, Bienengraeber MW, Kwok WM.) Anesthesiology. 2015 Apr;122(4):806-20 PMID: 25585005 PMCID: PMC4366337 01/15/2015
(Tewari SG, Zhou Y, Otto BJ, Dash RK, Kwok WM, Beard DA.) Front Physiol. 2014;5:513 PMID: 25628567 PMCID: PMC4292549 01/30/2015