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 basic mechanisms of cell death, and the roles of cell death in normal biology and human disease.
From a fundamental perspective, 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 to understand because the modalities of cell death have dramatically different consequences with respect to collateral tissue damage. We have discovered some regulators that unite apoptosis and necrosis signaling, and therefore may serve as "decision points". One is the cell death inhibitor ARC that antagonizes multiple apoptosis and necrosis pathways through mechanisms that we have delineated (Molecular Cell, 2004; PNAS, 2007; JBC, 2007; Cell Death Differ, 2014; others). Another is the BCL-2 protein BAX. While BAX has been long recognized for its role in permeabilization of the outer mitochondrial membrane during apoptosis, we have discovered that it plays an unexpected critical role in regulating necrosis through distinct mechanisms (PNAS, 2012). These studies have serendipitously led us to recognize that BAX regulates not only cell death, but also influences multiple critical mitochondrial functions including dynamics and mitophagy. We hypothesize that these effects are mediated by different conformations of BAX, an area we are currently pursuing.
While we have studied roles of cell death in cancer (Cell Death Differ, 2005; JBC, 2010; Cancer Res, 2011), diabetes (Diabetes, 2013), 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 heart syndromes: myocardial infarction and heart failure. The lab was one of the founders of the cardiac cell death field and has played a major role in its development (Annu Rev Physiol, 2010) including the first demonstrations that regulated forms of cell death play central roles in the pathogenesis of myocardial infarction (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 during myocardial infarction. While we have employed both unbiased 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 during myocardial infarction. In addition to traditional biochemical/molecular/cellular approaches, the latter work involves chemistry and structural biology (the latter in collaboration with Dr. Evripidis Gavathiotis) and small and large animal models.
I supervise a laboratory of approximately 10, 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.
Dorn GW 2nd, Kitsis RN. The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circ Res, 2015. 116: 167-182.
Song M, Gong G, Burelle Y, Gustafsson AB, Kitsis RN, Matkovich SJ, Dorn GW 2nd. Interdependence of Parkin-mediated mitophagy and mitochondrial fission in adult mouse heart. Circ Res, 2015. 117: 346-351.
Chen H, Ruiz PD, McKimpson WM, Novikov L, Kitsis RN, Gamble MJ. MacroH2A1 and ATM play opposing roles in paracrine senescence and senescence-associated secretory phenotype. Mol Cell, 2015. 59: 719-731.
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.
Linkermann A, Konstantinidis, Kitsis RN. Catch me if you can: targeting the mitochondrial permeability transition pore in myocardial infarction. Cell Death Differ, 2016. 23: 1-2.
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.
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