Cell Death: Fundamental Mechanisms and Roles in Human Disease
My lab studies (a) fundamental mechanisms of cell death and (b) the roles of cell death in human disease. Over the past 20 years, we have elucidated basic aspects of cell death biology, in particular delineating mechanisms by which the cell death inhibitor ARC antagonizes both the intrinsic and extrinsic death pathways (Molecular Cell, 2004. 15: 901-912; PNAS, 2007. 104: 20826-20831; JBC, 2007. 282: 5522-5528; JBC, 2007. 282: 5529-5535; others). Interestingly, we have discovered roles for ARC not only in heart disease, but also in cancer (Cell Death Differ, 2005; Cancer Res, 2011. 71: 7705-7715), pulmonary hypertension (Circulation, 2011. 124: 2533-2342), and type 2 diabetes (Diabetes, 2013: 62: 183-193).
Our most important translational accomplishments have focused on cell death in the heart. I was one of the founders of the cardiac cell death field and have played a leading role in its development. My lab was the first to demonstrate that regulated forms of cell death play a central role in the pathogenesis of myocardial infarction (J Mol Cell Cardiol, 2000. 32: 2397-2402 and others). In addition, we provided the first evidence that cell death is a causal component in the pathogenesis of heart failure (J Clin Invest, 2003. 111: 1497-1504 and others).
Presently, our work is focused on: (a) understanding mechanistic connections that link cell death programs - in particular, apoptosis and necrosis (PNAS, 2012. 109: 6566-6571; Cell Death Differ, 2014. 21: 634-644); and molecular connections between cell death and other mitochondrial processes. One of these processes, which plays important roles in aging and disease, is mitophagy, the selective elimination of senescent and damaged mitochondria by a specialized form of macroautophagy. Recently, we discovered new roles for cell death molecules as regulators of mitophagy. (b) A second major focus in the lab employs chemical and structural approaches in the identification/design of small molecules to reduce cardiomyocyte death. We have used both unbiased screening (Probe Reports from the NIH Molecular Libraries Program, 2013; PMID: 24404634) and candidate approaches to develop prototypes of what we hope will become small molecule drugs to reduce heart damage during myocardial infarction.
I supervise a laboratory of approximately 8, 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 11 individuals who have received the Ph.D. degree. A significant proportion of my trainees 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.
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.
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.
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.
Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA, Kitsis RN, Scherer, PE. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med, 2005. 11: 797-803.
Kitsis RN, Jialal I. Inhibiting CRP to limit myocardial damage during acute myocardial infarction? New Engl J Med, 2006. 355: 513-515.
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.
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.
Kitsis RN, Peng CF, Cuervo AM. Eat your heart out. Nat Med, 2007. 13: 539-541.
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.
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.
Park M, Shen YT, Gaussin V, Heyndrickx GR, Bartunek J, Resuello RG, Natividad FF, Kitsis RN, Vatner DE, Vatner SF.Apoptosis predominates in non-myocytes in heart failure. Am J Physiol Heart Circ Physiol, 2009. 297: H785-H791.
Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu Rev Physiol, 2010. 72: 19-44.
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.
Kung G, Konstantinidis K, Kitsis RN. Programmed necrosis – not apoptosis – in the heart. Circ Res, 2011. 108: 1017-1036. Circulation Research reports that this article was downloaded 1,990 times in the first 30 days of publication.
Feng D, Tang Y, Kwon H, Zong H, Hawkins M, Kitsis RN, Pessin, JE. High-fat diet-induced adipocyte cell death occurs through a cyclophilin D intrinsic signaling pathway independent of adipose tissue inflammation. Diabetes, 2011. 60: 2134-2143.
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.
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.
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.
Konstantinidis K, Kitsis RN. Escaped DNA inflames the heart. Nature, 2012. 485: 179-180.
Konstantinidis K, Whelan RS, Kitsis RN. Mechanisms of cell death in heart disease. Arterioscler Thromb Vasc Biol, 2012. 32: 1552-1562.
Gavrilov, S, Nuehrenberg TG, Ashton AW, Peng CF, Moore JC, Konstantinidis K, Mummery CL, Kitsis RN. Tbx6 is a determinant of cardiac and neural cell fate decisions in multipotent P19CL6 cells. Differentiation, 2012. 84: 176-184.
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.
Yang Y, Rodriguez J, Kitsis RN. A microRNA links prolactin to peripartum cardiomyopathy. J Clin Invest, 2013. 123: 1925-1927.
Davis J, Kwong JQ, Kitsis RN, Molkentin JD. Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle. PLoS One, 2013. 8: e82053.
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.
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.
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. Mol Cell (in press). PMID: 26300260
More Information About Dr. Richard Kitsis
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Forchheimer Building, Room G46
Bronx, NY 10461