Einstein/Montefiore Department of Medicine

Department Faculty

Dr. Richard N. Kitsis, M.D.

Richard N. Kitsis, M.D.

Professor, Department of Medicine (Cardiology)

Professor, Department of Cell Biology

The Dr. Gerald and Myra Dorros Chair in Cardiovascular Disease

Director, Wilf Family Cardiovascular Research Institute

Areas of Research: Fundamental mechanisms of cell death and roles in human disease

Professional Interests

Cell Death: Fundamental Mechanisms and Roles in Human Disease

The most basic decision that any cell makes is to grow, differentiate, or die.  Our laboratory studies fundamental mechanisms of cell death and the roles of cell death in normal biology and human disease.

Fundamental research  Twelve cell death programs have been recognized to date.  Little is understood regarding how they coordinate and integrate to produce a unified cell death response.  We have focused on two of these cell death programs, mitochondrial-mediated apoptosis and mitochondrial-mediated necrosis.  The defining molecular events that activate each of these programs take place within microns of each other at the outer and inner mitochondrial membranes respectively.  We are attempting to delineate how these cell death programs interconnect mechanistically and functionally.  We have identified proteins that unite apoptosis and necrosis signaling, and therefore may serve as "decision points" between these death programs.  One is the cell death inhibitor ARC that antagonizes multiple apoptosis and necrosis pathways (Molecular Cell, 2004; PNAS, 2007; JBC, 2007; Cell Death Differ, 2014).  Another is the BCL-2 protein BAX, which has been long recognized for its role in apoptosis and which we have discovered is critical for mitochondrial-mediated necrosis through distinct mechanisms (PNAS, 2012).  Also related to mitochondrial cell death signaling, other work in the lab is focused on understanding how alterations in the conformations of mitofusins regulate mitochondrial-ER interactions to impact metabolism and cell death (based on Nature, 2016; https://www.biorxiv.org/content/early/2018/04/17/301713; Science, 2018); and on functions of the F1-Fo mitochondrial ATP synthase.

Translational research  While we have studied roles of cell death in cancer (Cell Death Differ, 2005; JBC, 2010; Cancer Res, 2011; PLoS One, 2015), diabetes (Diabetes, 2013; Sci Rep, 2017; Developmental Cell, 2021), and pulmonary hypertension (Circulation, 2011), our most important translational accomplishments have focused on cell death in heart disease - specifically in the most common and lethal cardiac syndromes - myocardial infarction (heart attack) and heart failure.  Our lab was one of the founders of the cardiac cell death field and has played a major role in its development (Physiol Rev, 2019), including the first demonstrations that regulated forms of cell death play central roles in the pathogenesis of myocardial infarction (J Mol Cell Cardiol, 2000) and heart failure (J Clin Invest, 2003).  Currently, our translational work is focused on the chemical biology of cell death and, specifically, the development of small molecule drugs to inhibit apoptosis and necrosis.  We have employed both unbiased phenotypic screening of large chemical libraries (Probe Reports from the NIH Molecular Libraries Program, 2013) and target-based approaches.  The latter efforts have focused on BAX (Nat Chem Biol, 2019) because of its dual regulation of apoptosis and necrosis.  We are studying BAX inhibitors in several clinically relevant contexts including doxorubicin-induced cardiomyopathy (Nat Cancer, 2020).   

Our experimental approaches include biochemistry, molecular and cellular biology, the creation of genetic mouse models of disease; and, in collaboration with the Gavathiotis lab, chemical and structural approaches to small molecule drug design.

The laboratory currently consists of 12 individuals including one Instructor, one Research Scientist, 3 postdoctoral fellows, 6 graduate students (5 Ph.D. program; 1 M.D./Ph.D. program (NIH MSTP)), and one technician.   An important facet of my work is training and mentorship.  I have been thesis research advisor to 25 individuals who have received or are pursuing the Ph.D. degree, ~50 postdoctoral research fellows, and ~10 clinical fellows.  A significant proportion of my trainees have gone on to academic faculty positions as independent investigators and include a number of individuals from groups under-represented in science.

Selected Publications

Selected publications last 5 years and older publications as cited above:

McKimpson WM, Chen Y, Irving JA, Zheng M, Weinberger J, Tan WLW, Tiang Z, Jagger AM, Chua Jr SC, Pessin JE, Foo RSY, Lomas DA, Kitsis RN. Conversion of the death inhibitor ARC to a killer activates pancreatic β-cell death in diabetes.  Developmental Cell, 2021. 56:747-760.

Chelko SP, Keceli G, Carpi A, Doti N, Agrimi J, Asimaki A, Beti CB, Miyamoto M, Amat-Codina N, Bedja D, Wei A-C, Murray B, Tichnell C, Kwon C, Calkins H, James CA, O’Rourke B, Halushka MK, Melloni E,  Saffitz JE, Judge DP, Ruvo M, Kitsis RN, Andersen P, Di Lisa F, Paolocci N.  Exercise triggers CAPN1-mediated AIF truncation inducing myocyte necroptosis in arrhythmogenic cardiomyopathy. Sci Transl Med, 2021. 13(581):eabf0891.

Nakayama Y, Mukai N, Wang, BF, Yang K, Patwari P, Kitsis RN, Yoshioka J. Txnip C247S mutation protects the heart against acute myocardial infarction. J Mol Cell Cardiol, 2021. 155:36-49.

Moslehi J, Lichtman AH, Sharpe AH, Galluzzi L, Kitsis RN. Immune Checkpoint Inhibitor-Associated Myocarditis: Manifestations and Mechanisms. J Clin Invest, 2021. 131(5)e145186.

Tsai CH, Chang CY, Lin BZ, Wu, YL, Wu, MH, Lin LT, Huang WC, Holz JD, Sheu TJ, Lee JS, Kitsis RN, Tai PH, Lee YJ. Up-regulation of cofilin-1 in cell senescence associates with morphological change and p27kip1 mediated growth delay. Aging Cell, 2021. 20:e13288.

Chen F, Amgalan D, Kitsis RN, Pessin JE, Feng D.  ATG16L1 autophagy pathway regulates BAX protein levels and programmed cell death.  J Biol Chem, 2020.  295: 15045-15053.

Amgalan D, Garner TP, Pekson R, Jia XF, Yanamandala M, Paulino V, Liang FG, Corbalan JJ, Lee J, Chen Y, Karagiannis G, Sanchez LR, Liang H, Narayanagari SR, Mitchell K, Lopez A, Margulets V, Scarlata M, Santulli G, Asnani A, Peterson RT, Hazan RB, Condeelis JS, Oktay MH, Steidl U, Kirshenbaum LA, Gavathiotis E, Kitsis RN. A small molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy. Nat Cancer, 2020. 1:315-328.

Garner TP, Amgalan D, Reyna DE, Li S, Kitsis RN, Gavathiotis E. Small-molecule allosteric inhibitors of BAX. Nat Chem Biol, 2019. 15:322-330.

Del Re, DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN. Fundamental mechanisms of regulated cell death and implications for heart disease.  Physiol Rev, 2019. 99:1765-1817.

Feng D, Amgalan D, Singh R, Wei J, Wen J, Wei TP, McGraw TE, Kitsis RN, Pessin JE. SNAP23 regulates BAX-dependent adipocyte programmed cell death independently of canonical macroautophagy. J Clin Invest, 2018. 128:3941-3956.

Kushnir A, Santulli G, Reiken SR, Coromilas E, Godfrey SJ, Brunjes DL, Colombo PC, Yuzefpolskaya M, Sokol SI, Kitsis RN*, Marks AR*. Ryanodine receptor calcium leak in circulating B-lymphocytes as a biomarker in heart failure. Circulation, 2018. 138:1144-1154. *Equal contribution.

Rocha AG, Franco A, Krezel AM, Rumsey JM, Alberti JM, Knight WC, Biris N, Zacharioudakis E, Janetka JW, Baloh RH, Kitsis RN, Mochly-Rosen D, Townsend RR, Gavathiotis E, Dorn GW 2nd. MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A.  Science, 2018. 360:336-341.

Zacharioudakis E, Biris N, Garner T, Chen Y, Pekson R, Dhingra R, Santulli G, Kirshenbaum L, Kitsis R, Gavathiotis E. Direct Small Molecule Activation of Mitofusins. bioRxiv, 2018. https://www.biorxiv.org/content/early/2018/04/17/301713.

Suyama K, Yao J, Liang H, Benard O, Loudig OD, Amgalan D, McKimpson WM, Phillips GR, Segall J, Wang Y, Fineberg S, Norton L, Kitsis RN, Hazan RB. An Akt3 splice variant lacking the serine 472 phosphorylation site promotes apoptosis and suppresses mammary tumorigenesis.  Cancer Res, 2018. 78:103-114.

Wang Y, Wu B, Lu P, Zhang D, Wu B, Varshney S, Del Monte-Nieto G, Zhuang Z, Charafeddine R, Kramer AH, Sibinga NE, Frangogiannis NG, Kitsis RN, Adams RH, Alitalo K, Sharp DJ, Harvey RP, Stanley P, Zhou B.  Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1. Nat Commun, 2017. 8(1):578.

Templin AT, Samarasekera T, Meier DT, Hogan MF, Mellati M, Crow MT, Kitsis RN, Zraika S, Hull RL, Kahn SE.  Apoptosis repressor with caspase recruitment domain ameliorates amyloid-induced β-cell apoptosis by reducing JNK pathway activation. Diabetes, 2017. 66:2636-2645.

McKimpson WM, Zheng M, Chua Jr SC, Pessin JE, Kitsis RN.  ARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes.  Scientific Reports, 2017. 7:7019.

Stanley RF, Piszczatowski RT, Bartholdy B, Mitchell K, McKimpson WM, Narayanagari S, Walter D, Todorova TI, Hirsch C, Makishima H, Will B, McMahon C, Gritsman K, Maciejewski JP, Kitsis RN, Steidl U. A myeloid tumor suppressor role for NOL3J Exp Med, 2017. 214:753-771. 

Hammerling BC, Najor RH, Cortez MQ, Shires SE, Leon LJ, Gonzales ER, Boassa D, Phan S, Thor A, Jimenez RE, Li H, Kitsis RN, Dorn II GW, Sadoshima J, Ellisman MH, Gustafsson AB.  A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance.  Nat Commun, 2017. 8:14050.

Franco A*, Kitsis RN*, Fleischer JA, Gavathiotis E, Kornfeld OS, Gong G, Biris N, Benz A, Qvit N, Donnelly SK, Chen Y, Mennerick S, Hodgson L, Mochly-Rosen D, Dorn GW 2nd.  Correcting mitochondrial fusion by manipulating mitofusin conformations.  Nature, 2016. 540: 74-79. *Equal contribution.

Mera P, Laue K, Ferron M, Confavreux C, Wei J, Galán-Díez M, Lacampagne A, Mitchell SJ, Mattison JA, Chen Y, Bacchetta J, Szulc P, Kitsis RN, de Cabo R, Friedman RA, Torsitano C, McGraw TE, Puchowicz M, Kurland I, Karsenty G.  Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise.  Cell Metab, 2016. 23: 1078-1092.

McKimpson WM, Yuan Z, Zheng M, Crabtree JS, Libutti SK, Kitsis RN. The cell death inhibitor ARC is induced in a tissue-specific manner by deletion of the tumor suppressor gene Men1, but not required for tumor development and growth.  PLoS One, 2015. 10: e0145792.

Chen H, Ruiz PD, McKimpson WM, Novikov L, Kitsis RN, Gamble MJ.  MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype.  Molecular Cell, 2015. 59:719-731.

Kung G, Dai P, Deng L, Kitsis RN.  A novel role for the apoptosis inhibitor ARC in suppressing TNFα-induced regulated necrosis.  Cell Death Differ, 2014. 21: 634-644.

Kane A, Peddibhotla S, Maloney P, Mehta A, Hood B, Suyama E, Nguyen K, Vasile S, Leavitt L, Cheltsov A, Salaiwal S, Stonich D, Mangravita-Novo A, Vicchiarelli M, Smith LH, Diwan J, Chung TDY, Pinkerton AB, Hershberger P, Malany S, Kitsis RN.  Cardioprotective inhibitors of reperfusion injury.  Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-2012 Dec 10 [updated 2013 Mar 22]. PMID: 24404634.

McKimpson WM, Weinberger J, Czerski L, Zheng M, Crow MT, Pessin JE, Chua SC Jr, Kitsis RN. The apoptosis inhibitor ARC alleviates the ER stress response to promote beta-cell survival. Diabetes, 2013. 62: 183-193.

Whelan RS, Konstantinidis K, Wei AC, Chun Y, Reyna DE, Jha S, Yang Y, Calvert JW, Lindsten T, Thompson CB, Crow MT, Gavathiotis E, Dorn II GW 2nd, O’Rourke B, Kitsis RN. Bax regulates primary necrosis through mitochondrial dynamics. Proc Natl Acad Sci (USA), 2012. 109: 6566-6571.

Medina-Ramirez CM, Goswami S, Smirnova T, Bamira D, Benson B, Ferrick N, Segall J, Pollard JW, Kitsis RN. Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance. Cancer Res, 2011. 71: 7705-7715.

Zaiman A, Damico R, Thoms-Chesley A, Files DC, Kesari P, Johnston L, Swaim M, Mozhammel S, Myers AC, Halushka M, El-Haddad H, Shimoda LA, Peng CF, Hassoun PM, Champion HC, Kitsis RN, Crow MT. A critical role for the protein apoptosis repressor with caspase recruitment domain in hypoxia-induced pulmonary hypertension. Circulation, 2011. 124: 2533-2542.

Wu L, Nam YJ, Peng CF, Crow MT, Kitsis RN. Induction of the apoptosis inhibitor ARC by Ras in human cancers. J Biol Chem, 2010. 285: 19235-19245.

Foo RSY, Nam YJ, Ostreicher MJ, Metzl MD, Whelan RS, Peng CF, Ashton AW, Fu W, Mani K, Chin SF, Provenzano E, Ellis I, Figg N, Pinder S, Bennett MR, Caldas C, Kitsis RN. Regulation of p53 tetramerization and nuclear export by ARC. Proc Natl Acad Sci (USA), 2007. 104: 20826-20831.

Foo RSY, Chan LK, Kitsis RN, Bennett MR. Ubiquitination and degradation of the anti-apoptotic protein ARC by MDM2. J Biol Chem, 2007. 282: 5529-5535.

Nam YJ, Mani K, Wu L, Peng CF, Calvert JW, Foo RSY, Krishnamurthy B, Miao W, Ashton AW, Lefer DJ, Kitsis RN. The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant. J Biol Chem, 2007. 282: 5522-5528.

 Mercier I, Vuolo M, Madan R, Xue X, Levalley AJ, Ashton AW, Jasmin JF, Czaja MT, Lin EY, Armstrong RC, Pollard JW, Kitsis RN. ARC, an apoptosis suppressor limited to terminally differentiated cells, is induced in human breast cancer and confers chemo- and radiation-resistance. Cell Death Differ, 2005. 12: 682-686.

Nam YJ, Mani K, Ashton AW, Peng CF, Krishnamurthy B, Hayakawa Y, Lee P, Korsmeyer SJ, Kitsis RN. Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions. Mol Cell, 2004. 15: 901-912.

Wencker D, Chandra M, Nguyen KT, Miao W, Garantziotis S, Factor SM, Shirani J, Armstrong RC, Kitsis RN. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest, 2003. 111: 1497-1504.

Miao W, Luo Z, Kitsis RN*, Walsh K*.  Intracoronary, adenovirus-mediated Akt gene transfer in heart limits infarct size following ischemia-reperfusion injury in vivo.  J Mol Cell Cardiol, 2000. 32:2397-2402. *Equal contribution.


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