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Nika Danial, PhD


Researcher


Researcher

  • Assosciate Professor of Cell Biology, Harvard Medical School

Contact Information

  • Office Phone Number(617) 632-6436
  • Fax(617) 632-5363

Bio

Dr. Danial received her PhD from Columbia University in 1999, and then trained as a postdoctoral research fellow at Harvard Medical School and DFCI under the supervision of Dr. Stanley Korsmeyer. In 2003, she was promoted to instructor and recently was granted assistant professorship in the Department of Cell Biology at HMS and the Department of Cancer Biology at DFCI, where she studies the integration of glucose metabolism and apoptosis.

Research

Integration of Glucose Metabolism and Apoptosis

Cellular energy metabolism and the core apoptotic pathway are two major determinants of cellular survival. Growth and survival factors stimulate glycolysis and inhibit apoptosis. Consequently, growth factor withdrawal leads to metabolic decline marked by decreased glycolytic rate, lowered oxygen consumption, decreased ATP levels, and reduced protein synthesis. If not reversed, these metabolic changes ultimately lead to apoptosis. The BCL-2 family of proteins, which consists of both death agonists and antagonists, constitutes a critical control point in apoptosis residing immediately upstream to irreversible cellular damage, where family members control the release of apoptogenic factors from mitochondria. Consistent with their ability to control cellular survival, select BCL-2 family members have been shown to function as oncoproteins and tumor suppressors. Although these proteins are best known for their control of apoptosis, recent findings point to novel roles for multiple family members, including their involvement in normal mitochondrial physiology. Mitochondrial dysfunction - such as aberrations in the tricarboxylic acid (TCA) cycle and deficiencies in aerobic fuel metabolism - has been reported in select disease settings, including certain types of cancer and diabetes. The significance of cellular metabolism in cancer has long been recognized; furthermore, it has been noted that patients with diabetes exhibit a higher incidence of cancer, which raises the issue of whether aberrations in glucose homeostasis lead to tumor growth. The molecular underpinnings of these observations, however, have not been fully explored. We have conducted a large-scale proteomic analysis of liver mitochondrial complexes containing BCL-2 family proteins which revealed that BAD, one family member, resides in a large mitochondrial protein complex containing glucokinase (GK, hexokinase IV). Genetic tests further revealed that BAD may function both as a specialized apoptotic "sentinel" responding to abnormalities in glucose metabolism and as an integral regulator embedded in pathways of glucose sensing and utilization. We recently found that BAD impacts cellular bioenergetics by regulating the efficiency with which mitochondria metabolize glucose to generate ATP. Strikingly, both the apoptotic and the metabolic functions of BAD are governed by a common protein domain. We are actively investigating the molecular mechanisms and the intracellular milieu that determine which function of BAD predominates. The long-term goal of this line of investigation is to gain insight into whether the propensity of BAD to impact cellular metabolism and fuel utilization by mitochondria plays any role in tumorigenesis and to explore whether manipulating cellular bioenergetics could have therapeutic benefits.

Fu A, Danial NN. Grasping for aspartate in tumour metabolism. Nat Cell Biol. 2018 Jul; 20(7):738-739.
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Martínez-François JR, Fernández-Agüera MC, Nathwani N, Lahmann C, Burnham VL, Danial NN, Yellen G. BAD and KATP channels regulate neuron excitability and epileptiform activity. Elife. 2018 01 25; 7.
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Foley J, Burnham V, Tedoldi M, Danial NN, Yellen G. BAD knockout provides metabolic seizure resistance in a genetic model of epilepsy with sudden unexplained death in epilepsy. Epilepsia. 2018 01; 59(1):e1-e4.
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Norberg E, Lako A, Chen PH, Stanley IA, Zhou F, Ficarro SB, Chapuy B, Chen L, Rodig S, Shin D, Choi DW, Lee S, Shipp MA, Marto JA, Danial NN. Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets. Cell Death Differ. 2017 02; 24(2):251-262.
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Giménez-Cassina A, Danial NN. Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins. Trends Endocrinol Metab. 2015 Apr; 26(4):165-75.
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Ljubicic S, Polak K, Fu A, Wiwczar J, Szlyk B, Chang Y, Alvarez-Perez JC, Bird GH, Walensky LD, Garcia-Ocaña A, Danial NN. Phospho-BAD BH3 mimicry protects ß cells and restores functional ß cell mass in diabetes. Cell Rep. 2015 Feb 03; 10(4):497-504.
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Ribeiro SM, Giménez-Cassina A, Danial NN. Measurement of mitochondrial oxygen consumption rates in mouse primary neurons and astrocytes. Methods Mol Biol. 2015; 1241:59-69.
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Lo JC, Ljubicic S, Leibiger B, Kern M, Leibiger IB, Moede T, Kelly ME, Chatterjee Bhowmick D, Murano I, Cohen P, Banks AS, Khandekar MJ, Dietrich A, Flier JS, Cinti S, Blüher M, Danial NN, Berggren PO, Spiegelman BM. Adipsin is an adipokine that improves ß cell function in diabetes. Cell. 2014 Jul 03; 158(1):41-53.
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Schoumacher M, Hurov KE, Lehár J, Yan-Neale Y, Mishina Y, Sonkin D, Korn JM, Flemming D, Jones MD, Antonakos B, Cooke VG, Steiger J, Ledell J, Stump MD, Sellers WR, Danial NN, Shao W. Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling. Cancer Res. 2014 Jun 15; 74(12):3294-305.
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Akbay EA, Moslehi J, Christensen CL, Saha S, Tchaicha JH, Ramkissoon SH, Stewart KM, Carretero J, Kikuchi E, Zhang H, Cohoon TJ, Murray S, Liu W, Uno K, Fisch S, Jones K, Gurumurthy S, Gliser C, Choe S, Keenan M, Son J, Stanley I, Losman JA, Padera R, Bronson RT, Asara JM, Abdel-Wahab O, Amrein PC, Fathi AT, Danial NN, Kimmelman AC, Kung AL, Ligon KL, Yen KE, Kaelin WG, Bardeesy N, Wong KK. D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev. 2014 Mar 01; 28(5):479-90.
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Giménez-Cassina A, Garcia-Haro L, Choi CS, Osundiji MA, Lane EA, Huang H, Yildirim MA, Szlyk B, Fisher JK, Polak K, Patton E, Wiwczar J, Godes M, Lee DH, Robertson K, Kim S, Kulkarni A, Distefano A, Samuel V, Cline G, Kim YB, Shulman GI, Danial NN. Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metab. 2014 Feb 04; 19(2):272-84.
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Szlyk B, Braun CR, Ljubicic S, Patton E, Bird GH, Osundiji MA, Matschinsky FM, Walensky LD, Danial NN. A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Nat Struct Mol Biol. 2014 Jan; 21(1):36-42.
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Stanley IA, Ribeiro SM, Giménez-Cassina A, Norberg E, Danial NN. Changing appetites: the adaptive advantages of fuel choice. Trends Cell Biol. 2014 Feb; 24(2):118-27.
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Danial NN, Hartman AL, Stafstrom CE, Thio LL. How does the ketogenic diet work? Four potential mechanisms. J Child Neurol. 2013 Aug; 28(8):1027-33.
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Hassan S, Karpova Y, Baiz D, Yancey D, Pullikuth A, Flores A, Register T, Cline JM, D'Agostino R, Danial N, Datta SR, Kulik G. Behavioral stress accelerates prostate cancer development in mice. J Clin Invest. 2013 Feb; 123(2):874-86.
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Yan J, Xiang J, Lin Y, Ma J, Zhang J, Zhang H, Sun J, Danial NN, Liu J, Lin A. Inactivation of BAD by IKK inhibits TNFa-induced apoptosis independently of NF-?B activation. Cell. 2013 Jan 17; 152(1-2):304-15.
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Shah DI, Takahashi-Makise N, Cooney JD, Li L, Schultz IJ, Pierce EL, Narla A, Seguin A, Hattangadi SM, Medlock AE, Langer NB, Dailey TA, Hurst SN, Faccenda D, Wiwczar JM, Heggers SK, Vogin G, Chen W, Chen C, Campagna DR, Brugnara C, Zhou Y, Ebert BL, Danial NN, Fleming MD, Ward DM, Campanella M, Dailey HA, Kaplan J, Paw BH. Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. Nature. 2012 Nov 22; 491(7425):608-12.
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Caro P, Kishan AU, Norberg E, Stanley IA, Chapuy B, Ficarro SB, Polak K, Tondera D, Gounarides J, Yin H, Zhou F, Green MR, Chen L, Monti S, Marto JA, Shipp MA, Danial NN. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell. 2012 Oct 16; 22(4):547-60.
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Chae YC, Caino MC, Lisanti S, Ghosh JC, Dohi T, Danial NN, Villanueva J, Ferrero S, Vaira V, Santambrogio L, Bosari S, Languino LR, Herlyn M, Altieri DC. Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s. Cancer Cell. 2012 Sep 11; 22(3):331-44.
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Fu S, Fan J, Blanco J, Gimenez-Cassina A, Danial NN, Watkins SM, Hotamisligil GS. Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting. PLoS Genet. 2012 Aug; 8(8):e1002902.
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Giménez-Cassina A, Martínez-François JR, Fisher JK, Szlyk B, Polak K, Wiwczar J, Tanner GR, Lutas A, Yellen G, Danial NN. BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. Neuron. 2012 May 24; 74(4):719-30.
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Osundiji MA, Godes ML, Evans ML, Danial NN. BAD modulates counterregulatory responses to hypoglycemia and protective glucoprivic feeding. PLoS One. 2011; 6(12):e28016.
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Tinoco AD, Kim YG, Tagore DM, Wiwczar J, Lane WS, Danial NN, Saghatelian A. A peptidomics strategy to elucidate the proteolytic pathways that inactivate peptide hormones. Biochemistry. 2011 Mar 29; 50(12):2213-22.
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Gimenez-Cassina A, Danial NN. Noxa: a sweet twist to survival and more. Mol Cell. 2010 Dec 10; 40(5):687-8.
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Simarro M, Gimenez-Cassina A, Kedersha N, Lazaro JB, Adelmant GO, Marto JA, Rhee K, Tisdale S, Danial N, Benarafa C, Orduña A, Anderson P. Fast kinase domain-containing protein 3 is a mitochondrial protein essential for cellular respiration. Biochem Biophys Res Commun. 2010 Oct 22; 401(3):440-6.
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Danial NN, Gimenez-Cassina A, Tondera D. Homeostatic functions of BCL-2 proteins beyond apoptosis. Adv Exp Med Biol. 2010; 687:1-32.
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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. 2009 Feb 13; 33(3):377-88.
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Danial NN. BAD: undertaker by night, candyman by day. Oncogene. 2008 Dec; 27 Suppl 1:S53-70.
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Hettiarachchi KD, Zimmet PZ, Danial NN, Myers MA. Transplacental exposure to the vacuolar-ATPase inhibitor bafilomycin disrupts survival signaling in beta cells and delays neonatal remodeling of the endocrine pancreas. Exp Toxicol Pathol. 2008 Aug; 60(4-5):295-306.
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Danial NN, Walensky LD, Zhang CY, Choi CS, Fisher JK, Molina AJ, Datta SR, Pitter KL, Bird GH, Wikstrom JD, Deeney JT, Robertson K, Morash J, Kulkarni A, Neschen S, Kim S, Greenberg ME, Corkey BE, Shirihai OS, Shulman GI, Lowell BB, Korsmeyer SJ. Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med. 2008 Feb; 14(2):144-53.
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Danial NN. BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clin Cancer Res. 2007 Dec 15; 13(24):7254-63.
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Benz EJ, Nathan DG, Amaravadi RK, Danial NN. Targeting the cell death-survival equation. Clin Cancer Res. 2007 Dec 15; 13(24):7250-3.
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Wikstrom JD, Katzman SM, Mohamed H, Twig G, Graf SA, Heart E, Molina AJ, Corkey BE, de Vargas LM, Danial NN, Collins S, Shirihai OS. beta-Cell mitochondria exhibit membrane potential heterogeneity that can be altered by stimulatory or toxic fuel levels. Diabetes. 2007 Oct; 56(10):2569-78.
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Brunelle JK, Shroff EH, Perlman H, Strasser A, Moraes CT, Flavell RA, Danial NN, Keith B, Thompson CB, Chandel NS. Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death. Mol Cell Biol. 2007 Feb; 27(4):1222-35.
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Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS, Danial NN, De Strooper B, Scorrano L. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006 Jul 14; 126(1):177-89.
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Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A. 2005 Aug 23; 102(34):12005-10.
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Limnander A, Danial NN, Rothman PB. v-Abl signaling disrupts SOCS-1 function in transformed pre-B cells. Mol Cell. 2004 Aug 13; 15(3):329-41.
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Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004 Jan 23; 116(2):205-19.
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Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM, Datta SR, Greenberg ME, Licklider LJ, Lowell BB, Gygi SP, Korsmeyer SJ. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature. 2003 Aug 21; 424(6951):952-6.
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Ranger AM, Zha J, Harada H, Datta SR, Danial NN, Gilmore AP, Kutok JL, Le Beau MM, Greenberg ME, Korsmeyer SJ. Bad-deficient mice develop diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2003 Aug 05; 100(16):9324-9.
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Oki S, Limnander A, Danial NN, Rothman PB. Functional involvement of Akt signaling downstream of Jak1 in v-Abl-induced activation of hematopoietic cells. Blood. 2002 Aug 01; 100(3):966-73.
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Giallourakis C, Kashiwada M, Pan PY, Danial N, Jiang H, Cambier J, Coggeshall KM, Rothman P. Positive regulation of interleukin-4-mediated proliferation by the SH2-containing inositol-5'-phosphatase. J Biol Chem. 2000 Sep 22; 275(38):29275-82.
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Danial NN, Rothman P. JAK-STAT signaling activated by Abl oncogenes. Oncogene. 2000 May 15; 19(21):2523-31.
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Dorsch M, Danial NN, Rothman PB, Goff SP. A thrombopoietin receptor mutant deficient in Jak-STAT activation mediates proliferation but not differentiation in UT-7 cells. Blood. 1999 Oct 15; 94(8):2676-85.
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Harris MB, Chang CC, Berton MT, Danial NN, Zhang J, Kuehner D, Ye BH, Kvatyuk M, Pandolfi PP, Cattoretti G, Dalla-Favera R, Rothman PB. Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching. Mol Cell Biol. 1999 Oct; 19(10):7264-75.
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Danial NN, Losman JA, Lu T, Yip N, Krishnan K, Krolewski J, Goff SP, Wang JY, Rothman PB. Direct interaction of Jak1 and v-Abl is required for v-Abl-induced activation of STATs and proliferation. Mol Cell Biol. 1998 Nov; 18(11):6795-804.
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Dorsch M, Fan PD, Danial NN, Rothman PB, Goff SP. The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway. J Exp Med. 1997 Dec 15; 186(12):1947-55.
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Danial NN, Pernis A, Rothman PB. Jak-STAT signaling induced by the v-abl oncogene. Science. 1995 Sep 29; 269(5232):1875-7.
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