Nika N. Danial
Department of Pathology
Dana-Farber Cancer Institute
Center for Life Sciences 11-143
3 Blackfan Circle
Boston, MA 02115
Tel: (617) 632-6436
Fax: (617) 632-5363
Web Page: The Danial Lab Page
The primary focus of our laboratory is to delineate cellular energy and nutrient sensing pathways, including metabolic checkpoints that integrate cellular survival and bioenergetics. We employ a multi-disciplinary approach that draws on mouse genetics, mitochondrial physiology, shRNA library screens, chemical biology and proteomics to identify key metabolic pathways that determine the cell’s response to physiologic and pathophysiologic stress. The ultimate goal of this integrated approach is to uncover potential therapeutic targets in order to manipulate cellular energy metabolism in diseases such as cancer, diabetes and neurodegeneration.
We have recently discovered an unforeseen role for the pro-apoptotic BCL-2 protein BAD in mitochondrial metabolism of glucose. Several lines of evidence suggest that BAD serves as a checkpoint where bioenergetics and survival signaling pathways converge. Strikingly, the BH3 domain of BAD, previously known as its minimal death domain, is required and sufficient for mitochondrial oxidation of glucose. Structure/function analysis has shown that the BAD BH3 domain toggles between apoptosis and metabolism through a phosphorylation dependent mechanism, which inactivates its pro-apoptotic property while enabling its metabolic function. Furthermore, we have explored the pharmacologic relevance of phosphorylated BAD BH3 domain by demonstrating the metabolic activity of novel cell permeable chemically reinforced BAD BH3 helices. Our findings indicate that the BAD BH3 domain, previously only known for its apoptotic activity, has an alternative role in glucose oxidation, and warrant investigation into the molecular mechanisms and physiologic significance of this dual modality.
The implications of alternative physiologic roles for the BCL-2 proteins, such as BAD, are the subject of several ongoing projects in our laboratory. For example, we are currently exploring the functional significance of BAD’s dual role in apoptosis and glucose oxidation in pancreatic beta cells and neurons; two cell types whose proper function is tightly coupled with mitochondrial metabolism of glucose. We are also using several genetic models to assess how cellular metabolic cues, alone or parallel to other signal transduction pathways inform BAD’s dual functionalities in these cell types.
On a broader scale, the ramifications of our findings have led us to consider how the bioenergetic state of the cell, including ATP/ADP ratio and redox status, as well as the versatility of the mitochondrial metabolome to process alternate energy substrates such as carbohydrates, fatty acids and ketone bodies may feature in the manner the cells interpret and respond to stress stimuli. As such, one of our current projects is focused on targeting metabolism in a subset of B cell lymphoma with known alterations in mitochondrial genes.
Danial NN, Gramm CF, Scorrano L, Zhang C-Y, 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.
Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenki GV, Rudka T, Bartoli D, Polichuck RS, Danial NN, De Strooper B, Scorrano L. Opa1 controls apoptotic cristae remodeling independent form mitochondrial fusion. Cell 2006;126:177-89.
Danial NN, Walensky LD, Zhang C-Y, Choi CS, Fisher JK, Molina A, Datta SR, Pitter K, 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 pro-apoptotic BAD in insulin secretion and beta cell survival. Nat Med 2008;14:144-53.
Roy, S.S., Madesh, M., Davies, E., Antonsson, B., Danial, N.N., and Hajnoszky, 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, 2009.
BBS webpage updated 6/14/2010