• Researcher Profile

    Nika Danial, PhD

     
    Nika Danial, PhD
     
    Assosciate Professor of Cell Biology, Harvard Medical School

    Office phone: 617-632-6436
    Fax: 617-632-5363
    Email: nika_danial@dfci.harvard.edu

    Preferred contact method: email
     
     

    Research Department

    Cancer Biology

    Area of Research

    Integration of Glucose Metabolism and Apoptosis

    450 Brookline Avenue
    CLS 11-143
    Boston, MA 02215

    Biography

    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.

    Select Publications

    • 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;424:952-6.
    • Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004;116:205-19.
    • Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ. Cyclophilin D is an essential component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A 2005;102:12005-10.
    • 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;100:9324-9.
    • 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;14:144-53.
    • Roy SS, Madesh M, Davies E, Antonsson B, Danial N, Hajnczky G. Bad targets the permeability transition pore independent of Bax or Bak to switch between Ca2+-dependent cell survival and death. Mol Cell. 2009; 33:377-88.
    • Danial NN. BAD: undertaker by night, candyman by day.
      Oncogene. 2008; Suppl 1:S53-70.