BBS Faculty Member - Nika Danial

Nika Danial

Department of Cell Biology

Dana Farber Cancer Institute
Center for Life Sciences Building 11-143
3 Blackfan Circle
Boston, MA 02115
Tel: 617-632-6436
Fax: 617-632-5363
Visit my lab page here.

The focus of our laboratory is to decipher how metabolism of different carbon substrates (carbohydrates, fatty acids, amino acids and ketone bodies) modulates cellular stress responses. To this end, we employ a multi-disciplinary approach that draws on mouse genetics, mitochondrial physiology, chemical biology, proteomics and metabolomics. This research program has led to discoveries linking fuel metabolism to cellular stress outcomes that have implications for diabetes, seizure disorders and cancer.

Glucose-dependent modulation of beta-cell stress response: Insufficient beta-cell survival and insulin secretory response to glucose limit the benefits of beta-cell replacement/regeneration therapy. We have shown that phosphorylation of BAD, a protein with dual roles in apoptosis and metabolism, regulates both beta-cell glucose sensing and survival. This is mediated through direct activation of glucokinase (GK, hexokinase IV)- the MODY2 gene product- by the phosphorylated BAD BH3 helix. Beyond stimulation of insulin release, phospho-BAD protects beta-cell against stress stimuli that lead to beta-cell demise in diabetes. This protective effect requires GK-dependent increase in glucose flux and translates into increased donor islet survival and engraftment in transplanted diabetic mice. Efforts are underway to identify the glucose-dependent protective signal(s) in this setting. Our hypothesis is that increased glucose flux through phospho-BAD BH3 mimicry impinges on one or more aspects of beta-cell biology, in particular survival signaling, de-differentiation, and biosynthetic capacity, providing resistance to diabetes-related beta-cell dysfunction and death.

Metabolic control of neuronal activity by fuel substrate switching: Reciprocal utilization of glucose and ketone bodies alters neuronal excitability and modulate seizure sensitivity as evident from the seizure protective effect of low glycemic/ketogenic diets. However, the molecular underpinnings of the link between fuel utilization and neuronal activity have remained elusive, largely due to the complex and systemic effects of dietary manipulations. We have found that certain mutations in the Bad gene impart acute and cell-autonomous reciprocal effects on metabolism of glucose and ketone bodies in brain cells in the absence of any dietary manipulation. BAD variants that trigger a glucose-to-ketone body fuel switch produce resistance to behavioral and electrographic seizures by increasing the activity of metabolically sensitive KATP channels in neurons. Studies are underway to define the precise BAD-dependent metabolic alterations that control neural fuel preference. In the fullness of time, these efforts may reveal new therapeutic strategies for the control of neuronal excitation in seizure disorders.

Metabolic heterogeneity in cancer: While the initial focus of the cancer metabolism field has been aerobic glycolysis (the Warburg effect), increasing evidence, including research in our lab, points to tumor metabolic circuitries beyond aerobic glycolysis. We have shown that molecular subtypes of Diffuse Large B-Cell Lymphoma (DLBCL), which dependent on the B-cell receptor (BCR) for survival, have greater glycolytic flux typical of the Warburg phenotype. Unlike BCR/Warburg-type DLBCLs, OxPhos-DLBCLs channel the majority of glucose-derived pyruvate into mitochondria, display elevated mitochondrial electron transport and fatty acid oxidation. These OxPhos-type programs enable BCR-independent survival, and are associated with targetable vulnerabilities that, in the fullness of time, may lead to novel DLBCL subtype-selective therapies. Current projects focus on delineating pathways in charge of differential contribution of mitochondria to the metabolic profile of DLBCL subsets.

Last Update: 8/10/2015


For a complete listing of publications click here.



Danial NN, Walensky LD, Zhang C-Y, et al. (2008). Dual role of pro-apoptotic BAD in insulin secretion and beta-cell survival. Nat. Med. 14:144-53.

Gimenez-Cassina A, Ramón Martínez-François J, Fisher JK, et al. (2012). BAD-dependent regulation of carbon substrate metabolism and KATP channel activity confers resistance to epileptic seizures.
Neuron 74:719-30.

Caro P, Kishan AU, Norberg E, et al. (2012). Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma.
Cancer Cell 22:547-60.

Szlyk, B., Braun, C. R., Ljubicic, S., et al. (2014). A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators.
Nat. Struct. Mol. Biol. 21:36-42.

Giménez-Cassina, A., Garcia-Haro, L., Choi, C.S., et al. (2014). Regulation of hepatic energy metabolism and gluconeogenesis by BAD.
Cell Metab. 19:272-84.

Ljubicic, S., Polak, K., Fu, A., et al. (2015). Phospho-BAD BH3 mimicry protects beta-cells and restores functional beta-cell mass in diabetes.
Cell Rep. 10:497-504.

© 2015 by the President and Fellows of Harvard College