Faculty Profile

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; molecular connections among death programs; development of small molecule drugs to manipulate cell death 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.

Basic science

We are interested in how different death programs (in particular, apoptosis and necrosis) interconnect at the molecular level, and the mechanisms that determine whether a cell will die through one or another pathway.  This is an important issue because different modalities of cell death have dramatically different consequences with respect to collateral damage to surrounding tissue.  We have discovered mechanisms 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; others).  Another is the BCL-2 protein BAX, which has been long recognized for its permeabilization of the outer mitochondrial membrane during apoptosis and that we have discovered also plays a critical role in regulating necrosis through distinct mechanisms involving mitochondrial dynamics (fission-fusion) (PNAS, 2012).  We hypothesize that these effects are mediated by different conformations of BAX, an area we are currently pursuing.  Related collaborative work has focused on understanding conformational events in the activation mitofusins, GTPases that mediate outer mitochondrial events in mitochondrial fusion (Nature, 2016; https://www.biorxiv.org/content/early/2018/04/17/301713; Science, 2018)

Translational research

While we have studied roles of cell death in cancer (Cell Death Differ, 2005; Cell Cycle, 2008; JBC, 2010; Cancer Res, 2011; PLoS One, 2015), diabetes (Diabetes, 2013; Sci Rep, 2017), 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 (reviewed in Annu Rev Physiol, 2010), including the first demonstrations that regulated forms of cell death play central roles in the pathogenesis of myocardial infarction (Circulation, 2000; J Mol Cell Cardiol, 2000; others) and heart failure (J Clin Invest, 2003; others).  Currently, our translational work is focused on the chemical biology of cell death and, specifically, the development of small molecule drugs to reduce heart damage from myocardial infarction and cancer therapies.  While we have employed unbiased phenotypic screening of large chemical libraries (Probe Reports from the NIH Molecular Libraries Program, 2013), our current focus is on the development of the first BAX inhibitors - the rationale being that BAX is a critical mediator of both necrotic and apoptotic cell death.  In addition to traditional biochemical/molecular/cellular approaches, the latter work involves chemistry, structural biology, and small and large animal models.  Our recent research, in collaboration with Dr. Evripidis Gavathiotis, has identified allosteric inhibitors of BAX that protect the heart against damage from traditional chemotherapy and targeted cancer drugs (Amgalan et al; Garner et al; both in revision).

I supervise a laboratory of approximately 12, including Ph.D. and M.D./Ph.D. students and postdocs.  An important facet of my work is training and mentorship.  I have been thesis research advisor to more than a dozen individuals who have received the Ph.D. degree, ~50 postdoctoral research fellows, and ~10 clinical fellows, a significant proportion of whom have gone on to academic faculty positions as independent investigators.  My pre- and postdoctoral trainees have included a substantial number of individuals from groups under-represented in science.

Selected Publications

Publications (primary research papers only) 2016-present, and older publications as cited above:

Chen Y, Paulino V, Zheng M, Garcia C, Lee J, Owusu-Ansah E, Li H, Cuervo AM, Kitsis RN. Regulation of mitochondrial function by chaperone-mediated autophagy (submitted).

Amgalan D, Garner TP, Pekson R, Yanamandala M, Paulino V, Corbalan JJ, Lee J, Liang H, Narayanagari SR, Mitchell K, Lopez A, Margulets V, Asnani A, Peterson RT, Hazan RB, Kirshenbaum LA, Steidl U, Gavathiotis E*, Kitsis RN*.  Small molecule allosteric inhibition of BAX protects against chemotherapy-induced cardiomyopathy (in revision). *Equal contribution.

Garner TP, Amgalan D, Reyna DE, Li S, Kitsis RN, Gavathiotis E. First-in-class allosteric BAX inhibitors target a novel site.  Nat Chem Biol (in press).

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.

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.
Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance.  Annu Rev Physiol, 2010. 72:19-44
Mercier I, Vuolo M, Jasmin J-F, Medina CM, Williams M, Mariadason JM, Qian H, Xue X, Pestell RG, Lisanti MP, Kitsis RN. ARC (Apoptosis Repressor with Caspase Recruitment Domain) is a novel marker of human colon cancer. Cell Cycle, 2008. 7: 1640-1647.
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.
Lee P, Sata M, Lefer DJ, Factor SM, Walsh K, Kitsis RN.  Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo.  Am J Physiol Heart Circ Physiol, 2003. 284:H456-63.
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.
Fujio Y, Nguyen T, Wencker D, Kitsis RN, Walsh K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation, 2000. 101:660-667.

Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.

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Research Information