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Madesh Muniswamy, PhD

Madesh Muniswamy , PhD

 

Assistant Professor, Biochemistry

Assistant Professor, Cardiovascular Research Center

Assistant Professor, Center for Translational Medicine

Telephone:  215-707-5465

Fax:  215-707-9890

Email: madeshm@temple.edu

 

Department of Biochemistry

Cardiovascular Research Center

Center for Translational Medicine

 

Educational Background:

 

BS, Biochemistry, University of Madras, India, 1991

 

MS, Biochemistry, University of Madras, India, 1993

 

PhD, Bio-Medical Sciences, The Wellcome Trust Research Laboratory, 1998

 

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Research Interests:

 

Mitochondria are biological engines which convert nutrients into a chemical energy that we call ATP. Under certain conditions aberrant mitochondrial function leads to oxidative stress. Oxidative stress is commonly associated with cellular dysfunction during inflammatory conditions, and leads to the development of ischemic injury and sepsis. My laboratory has been applying novel approaches to identify the mechanisms by which superoxide anion (O2•-), a reactive oxygen species (ROS), selectively potentiates pathophysiological endothelial signaling during oxidative stress. Recently, our lab discovered a unique role for O2•- in perturbation of endothelial Ca2+ homeostasis. Specifically, O2•- led an elevation in intracellular calcium [Ca2+]i via inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3R) on the endoplasmic reticulum, resulting in mitochondrial dysfunction and endothelial apoptosis. Our lab has also developed a model in which O2•- can stimulate endothelial signaling independent of inflammatory cytokines and other paracrine factors. To translate this in vitro model and test our hypothesis in vivo, we have developed means to image endothelial signaling in both lung slices and intact organs. Based on these novel approaches, we are currently focusing on the role of O2•- in endothelial homeostasis and endoplasmic reticulum (ER) Ca2+ signaling.

 

Muniswamy research interestes


We have also utilized whole-genome shRNA screening to identify candidate molecules that promote lung cell death and chronic obstructive pulmonary disease (COPD) in response to cigarette smoke, inflammation and infection. COPD is the fourth most-prevalent chronic disease in the United States, and is largely caused by smoking. Lung cell injury and death in COPD likely results from a variety of stressors including cigarette smoke, bacterial pathogens and cytokines like interferon g. In turn, lung cell injury and death are believed to underlie COPD exacerbations and progression of the disease. Our lab has identified several previously undescribed candidate molecules involved in cell death during COPD.

 

During these years, my lab made three seminal discoveries using comprehensive high-throughput screening. For instance, the observation in 1961 by two independent groups insisted that the power house of the cell, the mitochondrion, acts as a sponge and takes up huge amounts of external Ca2+ through an unknown pathway later named as a uniporter. Since then, researchers believed that mitochondria have the capacity to take up enormous amounts of Ca2+ through this uniporter to regulate cellular Ca2+ homeostasis. Nevertheless, the proposed concept of a mitochondrial Ca2+ set-point (year 1978) suggested that mitochondria in cells at rest maintain very low levels of Ca2+ by an unknown mechanism. My laboratory demonstrated that the mitochondrial inner membrane protein MICU1 interacts with and guards the mitochondrial uniporter channel pore subunit MCU from Ca2+ permeation (Cell, October 2012). Without this mechanism, mitochondria accumulate excessive Ca2+ resulting in oxidative stress and increased sensitization to cell death in several cell types including endothelial cells. Additionally, our Nature Cell Biology (highlights in Nature Reviews Molecular Cell Biology) paper published in December 2012 identified a novel mitochondrial inner membrane protein that we named as MCUR1 (mitochondrial Ca2+ Uniporter Regulator 1). We found that MCUR1 positively regulates MCU (channel pore). Notably, these molecules have been sought for over five decades. Two years ago, my laboratory discovered the ROS sensing role of STIM1, distinct from its Ca2+ sensing function (Journal of Cell Biology 2010). Based on the role of STIM1 as a ROS sensor in addition to its ER Ca2+ sensing effect, I generated endothelial specific STIM1 KO mice that were protected against LPS-induced vascular inflammation, a finding that was published in the current issue of Journal of Clinical Investigation, 2013 (Commentary and JCI impact). In summation, our very recent discovery demonstrated that a mitochondrial resident transmembrane protein Mitochondrial Ca2+ Uniporter Regulator 1 (MCUR1) is essential for Mitochondrial Ca2+ Uniporter (MCU)-mediated mitochondrial Ca2+ uptake (Nature Cell Biology, 2012). These components were unknown for over five decades. We also identified the molecular component (Mitochondrial Ca2+ Uptake 1; MICU1) that controls the mitochondrial Ca2+ uptake “set point”, a concept known but uncharacterized for over thirty years (Cell, 2012). Identification of these major Ca2+ signaling components in my laboratory uniquely places us in a privileged position to investigate the mitochondrial bioenergetics both in physiology and in major pathological settings including cardiovascular, cancer, neurodegenerative and metabolic diseases.

 

 

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professional organizations:

 

  • American Society for Biochemistry and Molecular Biology
  • American Association for the Advancement of Science
  • American Association for Cancer Research
  • American Society of Microbiology

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PUBMED PUBLICATIONS :


Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

24492610. Miller BA, Hoffman NE, Merali S, Zhang XQ, Wang J, Rajan S, Shanmughapriya S, Gao E, Barrero CA, Mallilankaraman K, Song J, Gu T, Hirschler-Laszkiewicz I, Koch WJ, Feldman AM, Madesh M, Cheung JY, TRPM2 Channels Protect against Cardiac Ischemia-Reperfusion Injury: ROLE OF MITOCHONDRIA. J Biol Chem 289:11(7615-29)2014 Mar 14

24469450. Bánsághi S, Golenár T, Madesh M, Csordás G, Ramachandrarao S, Sharma K, Yule DI, Joseph SK, Hajnóczky G, Isoform- and Species-specific Control of Inositol 1,4,5-Trisphosphate (IP3) Receptors by Reactive Oxygen Species. J Biol Chem 289:12(8170-81)2014 Mar 21

24430870. Hoffman NE, Chandramoorthy HC, Shanmughapriya S, Zhang XQ, Vallem S, Doonan PJ, Malliankaraman K, Guo S, Rajan S, Elrod JW, Koch WJ, Cheung JY, Madesh M, SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death. Mol Biol Cell 25:6(936-47)2014 Mar

24401846. Deliu E, Brailoiu GC, Eguchi S, Hoffman NE, Rabinowitz JE, Tilley DG, Madesh M, Koch WJ, Brailoiu E, Direct evidence of intracrine angiotensin II signaling in neurons. Am J Physiol Cell Physiol 306:8(C736-44)2014 Apr

24377350. Sharma VD, Lees J, Hoffman NE, Brailoiu E, Madesh M, Wunder SL, Ilies MA, Modulation of Pyridinium Cationic Lipid-DNA Complex Properties by Pyridinium Gemini Surfactants and Its Impact on Lipoplex Transfection Properties. Mol Pharm :()2014 Jan 6

24332854. Hoffman NE, Chandramoorthy HC, Shamugapriya S, Zhang X, Rajan S, Mallilankaraman K, Gandhirajan RK, Vagnozzi RJ, Ferrer LM, Sreekrishnanilayam K, Natarajaseenivasan K, Vallem S, Force T, Choi ET, Cheung JY, Madesh M, MICU1 motifs define mitochondrial calcium uniporter binding and activity. Cell Rep 5:6(1576-88)2013 Dec 26

24170934. Huang ZM, Gao E, Fonseca FV, Hayashi H, Shang X, Hoffman NE, Chuprun JK, Tian X, Tilley DG, Madesh M, Lefer DJ, Stamler JS, Koch WJ, Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury. Sci Signal 6:299(ra95)2013 Oct 29

24132636. Vagnozzi RJ, Gatto GJ Jr, Kallander LS, Hoffman NE, Mallilankaraman K, Ballard VL, Lawhorn BG, Stoy P, Philp J, Graves AP, Naito Y, Lepore JJ, Gao E, Madesh M, Force T, Inhibition of the cardiomyocyte-specific kinase TNNI3K limits oxidative stress, injury, and adverse remodeling in the ischemic heart. Sci Transl Med 5:207(207ra141)2013 Oct 16

23924319. Barrero CA, Perez-Leal O, Aksoy M, Moncada C, Ji R, Lopez Y, Mallilankaraman K, Madesh M, Criner GJ, Kelsen SG, Merali S, Histone 3.3 participates in a self-sustaining cascade of apoptosis that contributes to the progression of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 188:6(673-83)2013 Sep 15

23814062. Yu J, Deliu E, Zhang XQ, Hoffman NE, Carter RL, Grisanti LA, Brailoiu GC, Madesh M, Cheung JY, Force T, Abood ME, Koch WJ, Tilley DG, Brailoiu E, Differential activation of cultured neonatal cardiomyocytes by plasmalemmal versus intracellular G protein-coupled receptor 55. J Biol Chem 288:31(22481-92)2013 Aug 2

23801066. Duran JM, Makarewich CA, Sharp TE, Starosta T, Zhu F, Hoffman NE, Chiba Y, Madesh M, Berretta RM, Kubo H, Houser SR, Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms. Circ Res 113:5(539-52)2013 Aug 16

23376831. Miller BA, Wang J, Hirschler-Laszkiewicz I, Gao E, Song J, Zhang XQ, Koch WJ, Madesh M, Mallilankaraman K, Gu T, Chen SJ, Keefer K, Conrad K, Feldman AM, Cheung JY, The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 304:7(H1010-22)2013 Apr 1

23348743. Gandhirajan RK, Meng S, Chandramoorthy HC, Mallilankaraman K, Mancarella S, Gao H, Razmpour R, Yang XF, Houser SR, Chen J, Koch WJ, Wang H, Soboloff J, Gill DL, Madesh M, Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. J Clin Invest 123:2(887-902)2013 Feb 1

23276949. Yin Y, Pastrana JL, Li X, Huang X, Mallilankaraman K, Choi ET, Madesh M, Wang H, Yang XF, Inflammasomes: sensors of metabolic stresses for vascular inflammation. Front Biosci (Landmark Ed) 18:(638-49)2013 Jan 1

23239879. Pan JA, Fan Y, Gandhirajan RK, Madesh M, Zong WX, Hyperactivation of the mammalian degenerin MDEG promotes caspase-8 activation and apoptosis. J Biol Chem 288:5(2952-63)2013 Feb 1

23178883. Mallilankaraman K, Cárdenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenár T, Csordás G, Madireddi P, Yang J, Müller M, Miller R, Kolesar JE, Molgó J, Kaufman B, Hajnóczky G, Foskett JK, Madesh M, MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14:12(1336-43)2012 Dec

23159931. Mancarella S, Potireddy S, Wang Y, Gao H, Gandhirajan RK, Autieri M, Scalia R, Cheng Z, Wang H, Madesh M, Houser SR, Gill DL, Targeted STIM deletion impairs calcium homeostasis, NFAT activation, and growth of smooth muscle. FASEB J 27:3(893-906)2013 Mar

23101630. Mallilankaraman K, Doonan P, Cárdenas C, Chandramoorthy HC, Müller M, Miller R, Hoffman NE, Gandhirajan RK, Molgó J, Birnbaum MJ, Rothberg BS, Mak DO, Foskett JK, Madesh M, MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 151:3(630-44)2012 Oct 26

23086942. Deliu E, Brailoiu GC, Mallilankaraman K, Wang H, Madesh M, Undieh AS, Koch WJ, Brailoiu E, Intracellular endothelin type B receptor-driven Ca2+ signal elicits nitric oxide production in endothelial cells. J Biol Chem 287:49(41023-31)2012 Nov 30

22914293. Soboloff J, Rothberg BS, Madesh M, Gill DL, STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol 13:9(549-65)2012 Sep

22250084. Kato K, Lillehoj EP, Park YS, Umehara T, Hoffman NE, Madesh M, Kim KC, Membrane-tethered MUC1 mucin is phosphorylated by epidermal growth factor receptor in airway epithelial cells and associates with TLR5 to inhibit recruitment of MyD88. J Immunol 188:4(2014-22)2012 Feb 15

22215029. Mallilankaraman K, Gandhirajan RK, Hawkins BJ, Madesh M, Visualization of vascular Ca2+ signaling triggered by paracrine derived ROS. J Vis Exp :58()2011 Dec 21

22084246. Mancarella S, Wang Y, Deng X, Landesberg G, Scalia R, Panettieri RA, Mallilankaraman K, Tang XD, Madesh M, Gill DL, Hypoxia-induced acidosis uncouples the STIM-Orai calcium signaling complex. J Biol Chem 286:52(44788-98)2011 Dec 30

21769090. Soboloff J, Madesh M, Gill DL, Sensing cellular stress through STIM proteins. Nat Chem Biol 7:8(488-92)2011 Jul 18

21746883. Irrinki KM, Mallilankaraman K, Thapa RJ, Chandramoorthy HC, Smith FJ, Jog NR, Gandhirajan RK, Kelsen SG, Houser SR, May MJ, Balachandran S, Madesh M, Requirement of FADD, NEMO, and BAX/BAK for aberrant mitochondrial function in tumor necrosis factor alpha-induced necrosis. Mol Cell Biol 31:18(3745-58)2011 Sep

21653942. Cheng Z, Jiang X, Kruger WD, Praticň D, Gupta S, Mallilankaraman K, Madesh M, Schafer AI, Durante W, Yang X, Wang H, Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor-mediated vasorelaxation in transgenic cystathionine beta synthase-deficient mice. Blood 118:7(1998-2006)2011 Aug 18

21576359. Thapa RJ, Basagoudanavar SH, Nogusa S, Irrinki K, Mallilankaraman K, Slifker MJ, Beg AA, Madesh M, Balachandran S, NF-kappaB protects cells from gamma interferon-induced RIP1-dependent necroptosis. Mol Cell Biol 31:14(2934-46)2011 Jul

20876534. Brailoiu GC, Gurzu B, Gao X, Parkesh R, Aley PK, Trifa DI, Galione A, Dun NJ, Madesh M, Patel S, Churchill GC, Brailoiu E, Acidic NAADP-sensitive calcium stores in the endothelium: agonist-specific recruitment and role in regulating blood pressure. J Biol Chem 285:48(37133-7)2010 Nov 26

20876216. Shuvaev VV, Han J, Yu KJ, Huang S, Hawkins BJ, Madesh M, Nakada M, Muzykantov VR, PECAM-targeted delivery of SOD inhibits endothelial inflammatory response. FASEB J 25:1(348-57)2011 Jan

20679432. Hawkins BJ, Irrinki KM, Mallilankaraman K, Lien YC, Wang Y, Bhanumathy CD, Subbiah R, Ritchie MF, Soboloff J, Baba Y, Kurosaki T, Joseph SK, Gill DL, Madesh M, S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. J Cell Biol 190:3(391-405)2010 Aug 9

20566649. Hawkins BJ, Levin MD, Doonan PJ, Petrenko NB, Davis CW, Patel VV, Madesh M, Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss. J Biol Chem 285:34(26494-505)2010 Aug 20

19897030. Davis CW, Hawkins BJ, Ramasamy S, Irrinki KM, Cameron BA, Islam K, Daswani VP, Doonan PJ, Manevich Y, Madesh M, Nitration of the mitochondrial complex I subunit NDUFB8 elicits RIP1- and RIP3-mediated necrosis. Free Radic Biol Med 48:2(306-17)2010 Jan 15

19855129. Levin MD, Lu MM, Petrenko NB, Hawkins BJ, Gupta TH, Lang D, Buckley PT, Jochems J, Liu F, Spurney CF, Yuan LJ, Jacobson JT, Brown CB, Huang L, Beermann F, Margulies KB, Madesh M, Eberwine JH, Epstein JA, Patel VV, Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers. J Clin Invest 119:11(3420-36)2009 Nov

19332555. Madesh M, Zong WX, Hawkins BJ, Ramasamy S, Venkatachalam T, Mukhopadhyay P, Doonan PJ, Irrinki KM, Rajesh M, Pacher P, Thompson CB, Execution of superoxide-induced cell death by the proapoptotic Bcl-2-related proteins Bid and Bak. Mol Cell Biol 29:11(3099-112)2009 Jun

19329538. Kolla V, Gonzales LW, Bailey NA, Wang P, Angampalli S, Godinez MH, Madesh M, Ballard PL, Carcinoembryonic cell adhesion molecule 6 in human lung: regulated expression of a multifunctional type II cell protein. Am J Physiol Lung Cell Mol Physiol 296:6(L1019-30)2009 Jun

19217411. Roy SS, Madesh M, Davies E, Antonsson B, Danial N, Hajnóczky G, Bad targets the permeability transition pore independent of Bax or Bak to switch between Ca2+-dependent cell survival and death. Mol Cell 33:3(377-88)2009 Feb 13

18648233. Yang H, Liang G, Hawkins BJ, Madesh M, Pierwola A, Wei H, Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies. Anesthesiology 109:2(243-50)2008 Aug

18573285. Milovanova T, Chatterjee S, Hawkins BJ, Hong N, Sorokina EM, Debolt K, Moore JS, Madesh M, Fisher AB, Caveolae are an essential component of the pathway for endothelial cell signaling associated with abrupt reduction of shear stress. Biochim Biophys Acta 1783:10(1866-75)2008 Oct

18212570. Wei H, Liang G, Yang H, Wang Q, Hawkins B, Madesh M, Wang S, Eckenhoff RG, The common inhalational anesthetic isoflurane induces apoptosis via activation of inositol 1,4,5-trisphosphate receptors. Anesthesiology 108:2(251-60)2008 Feb

17950837. Dziubla TD, Shuvaev VV, Hong NK, Hawkins BJ, Madesh M, Takano H, Simone E, Nakada MT, Fisher A, Albelda SM, Muzykantov VR, Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies. Biomaterials 29:2(215-27)2008 Jan

17853886. Mukhopadhyay P, Rajesh M, Haskó G, Hawkins BJ, Madesh M, Pacher P, Simultaneous detection of apoptosis and mitochondrial superoxide production in live cells by flow cytometry and confocal microscopy. Nat Protoc 2:9(2295-301)2007

17724077. Hawkins BJ, Solt LA, Chowdhury I, Kazi AS, Abid MR, Aird WC, May MJ, Foskett JK, Madesh M, G protein-coupled receptor Ca2+-linked mitochondrial reactive oxygen species are essential for endothelial/leukocyte adherence. Mol Cell Biol 27:21(7582-93)2007 Nov

17692540. Jones RG, Bui T, White C, Madesh M, Krawczyk CM, Lindsten T, Hawkins BJ, Kubek S, Frauwirth KA, Wang YL, Conway SJ, Roderick HL, Bootman MD, Shen H, Foskett JK, Thompson CB, The proapoptotic factors Bax and Bak regulate T Cell proliferation through control of endoplasmic reticulum Ca(2+) homeostasis. Immunity 27:2(268-80)2007 Aug

17540762. Cheong N, Zhang H, Madesh M, Zhao M, Yu K, Dodia C, Fisher AB, Savani RC, Shuman H, ABCA3 is critical for lamellar body biogenesis in vivo. J Biol Chem 282:33(23811-7)2007 Aug 17

17360969. Hawkins BJ, Madesh M, Kirkpatrick CJ, Fisher AB, Superoxide flux in endothelial cells via the chloride channel-3 mediates intracellular signaling. Mol Biol Cell 18:6(2002-12)2007 Jun

16429131. Muthumani K, Choo AY, Zong WX, Madesh M, Hwang DS, Premkumar A, Thieu KP, Emmanuel J, Kumar S, Thompson CB, Weiner DB, The HIV-1 Vpr and glucocorticoid receptor complex is a gain-of-function interaction that prevents the nuclear localization of PARP-1. Nat Cell Biol 8:2(170-9)2006 Feb

16415354. Cheong N, Madesh M, Gonzales LW, Zhao M, Yu K, Ballard PL, Shuman H, Functional and trafficking defects in ATP binding cassette A3 mutants associated with respiratory distress syndrome. J Biol Chem 281:14(9791-800)2006 Apr 7

16186254. Madesh M, Hawkins BJ, Milovanova T, Bhanumathy CD, Joseph SK, Ramachandrarao SP, Sharma K, Kurosaki T, Fisher AB, Selective role for superoxide in InsP3 receptor-mediated mitochondrial dysfunction and endothelial apoptosis. J Cell Biol 170:7(1079-90)2005 Sep 26

16179951. White C, Li C, Yang J, Petrenko NB, Madesh M, Thompson CB, Foskett JK, The endoplasmic reticulum gateway to apoptosis by Bcl-X(L) modulation of the InsP3R. Nat Cell Biol 7:10(1021-8)2005 Oct

16107509. Milovanova T, Chatterjee S, Manevich Y, Kotelnikova I, Debolt K, Madesh M, Moore JS, Fisher AB, Lung endothelial cell proliferation with decreased shear stress is mediated by reactive oxygen species. Am J Physiol Cell Physiol 290:1(C66-76)2006 Jan

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