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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

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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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.

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.

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

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

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 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, Praticò 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

15937149. Kazerounian S, Pitari GM, Shah FJ, Frick GS, Madesh M, Ruiz-Stewart I, Schulz S, Hajnóczky G, Waldman SA, Proliferative signaling by store-operated calcium channels opposes colon cancer cell cytostasis induced by bacterial enterotoxins. J Pharmacol Exp Ther 314:3(1013-22)2005 Sep

12876066. Sharma K, Deelman L, Madesh M, Kurz B, Ciccone E, Siva S, Hu T, Zhu Y, Wang L, Henning R, Ma X, Hajnoczky G, Involvement of transforming growth factor-beta in regulation of calcium transients in diabetic vascular smooth muscle cells. Am J Physiol Renal Physiol 285:6(F1258-70)2003 Dec

12865429. Hegde R, Srinivasula SM, Datta P, Madesh M, Wassell R, Zhang Z, Cheong N, Nejmeh J, Fernandes-Alnemri T, Hoshino S, Alnemri ES, The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein. J Biol Chem 278:40(38699-706)2003 Oct 3

12729578. Hajnóczky G, Davies E, Madesh M, Calcium signaling and apoptosis. Biochem Biophys Res Commun 304:3(445-54)2003 May 9

11980717. Csordás G, Madesh M, Antonsson B, Hajnóczky G, tcBid promotes Ca(2+) signal propagation to the mitochondria: control of Ca(2+) permeation through the outer mitochondrial membrane. EMBO J 21:9(2198-206)2002 May 1

11934702. McGowan TA, Madesh M, Zhu Y, Wang L, Russo M, Deelman L, Henning R, Joseph S, Hajnoczky G, Sharma K, TGF-beta-induced Ca(2+) influx involves the type III IP(3) receptor and regulates actin cytoskeleton. Am J Physiol Renal Physiol 282:5(F910-20)2002 May

11741882. Madesh M, Antonsson B, Srinivasula SM, Alnemri ES, Hajnóczky G, Rapid kinetics of tBid-induced cytochrome c and Smac/DIABLO release and mitochondrial depolarization. J Biol Chem 277:7(5651-9)2002 Feb 15

11739410. Madesh M, Hajnóczky G, VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid and massive cytochrome c release. J Cell Biol 155:6(1003-15)2001 Dec 10

11115374. Hajnóczky G, Csordás G, Madesh M, Pacher P, Control of apoptosis by IP(3) and ryanodine receptor driven calcium signals. Cell Calcium 28:5-6(349-63)2000 Nov-Dec

11080252. Hajnóczky G, Csordás G, Madesh M, Pacher P, The machinery of local Ca2+ signalling between sarco-endoplasmic reticulum and mitochondria. J Physiol 529 Pt 1:(69-81)2000 Nov 15

10836991. Sharma K, Mc Gowan TA, Wang L, Madesh M, Kaspar V, Szalai G, Thomas AP, Hajnóczky G, Inhibition of type I and III IP(3)Rs by TGF-beta is associated with impaired calcium release in mesangial cells. Am J Physiol Renal Physiol 278:6(F1022-9)2000 Jun

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