Nika N. Danial


Department of Pathology
Dana-Farber Cancer Institute
Smith Building, Room 758
44 Binney Street
Boston, MA 02115
Tel: (617) 632-6436
Fax: (617) 632-6401
Email: nika_danial@dfci.harvard.edu

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.  In addition, we are devising chemical and proteomic approaches to capture novel BAD BH3 ligands.  On a broader scale, the ramifications of our findings have led us to consider how mitochondrial fuel oxidation may affect cellular function and stress responses.  As such, one of the current projects in the laboratory is focused on targeting metabolism in a subset of B cell lymphoma with known alterations in mitochondrial genes.

 

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BBS webpage updated 12/02/2009