Mitochondrial Function, Islet Function & Stem Cells

Group Head: Andreas Wiederkehr, Ph.D. Contact

Teams:
Islet Function: Team Leader: Elhadji Dioum, Ph.D. Contact
Stem Cells: Team Leader: Marine Kraus Ph.D. Contact

 

Mitochondrial Function

Mitochondrial dysfunction is one of the main underlying causes of chronic diseases such as metabolic syndrome, type 2 diabetes and neurodegenerative diseases. In addition, mitochondrial function declines with age. The mission of the Mitochondrial Function group is to develop methods to assess mitochondrial function and apply them to the study of chronic diseases and aging. The group focuses on mitochondrial signalling events that adapt energy metabolism to the hormonal and nutrient status of the cell. These control mechanisms can be exploited to identify nutrients and bioactives that prevent mitochondrial dysfunction in specific tissues as a result of diseases progression or aging. Our group is using live-cell imaging, basic biochemistry and proteomics to study mitochondrial function.

Key Goals

  • Deliver methods for the study of mitochondrial function.
  • Identify nutritional approaches that improve mitochondrial function and slow chronic disease processes in the ageing population.
  • Provide novel evidence linking nutrients to the regulation of mitochondrial activity.
  • Develop research on mitochondrial signal transduction in neurons, astrocytes and pancreatic beta-cells.

 

Key Publications of the Group*

Santo-Domingo J, Chareyron I, Dayon L, Núñez Galindo A, Cominetti O, Pilar Giner Giménez M, De Marchi U, Canto C, Kussmann M, Wiederkehr A. (2017) Coordinated activation of mitochondrial respiration and exocytosis mediated by PKC signaling in pancreatic b-cells. FASEB J. 31(3):1028-1045.

Thevenet J, De Marchi U, Domingo JS, Christinat N, Bultot L, Lefebvre G, Sakamoto K, Descombes P, Masoodi M, Wiederkehr A. (2016) Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems. FASEB J. 30(5):1913-26.

De Marchi U, Thevenet J, Hermant A, Dioum E, Wiederkehr A. (2014) Calcium co-regulates oxidative metabolism and ATP synthase-dependent respiration in pancreatic beta cells. J Biol Chem. 289(13):9182-94.

Quan X, Nguyen TT, Choi SK, Xu S, Das R, Cha SK, Kim N, Han J, Wiederkehr A, Wollheim CB, Park KS. (2015) Essential role of mitochondrial Ca2+ uniporter in the generation of mitochondrial pH gradient and metabolism-secretion coupling in insulin-releasing cells. J Biol Chem. 290(7):4086-96.

Wiederkehr A, Wollheim CB. (2012) Mitochondrial signals drive insulin secretion in the pancreatic β-cell. Mol Cell Endocrinol. 353(1-2):128-37.

 

 

Islet Function

Team Leader: Elhadji Dioum, Ph.D. Contact

The main purpose of the Islet Function group is to identify and characterize novel G protein-coupled receptors (GPCRs) and signaling molecules that regulate pancreatic β-cell function and maintenance, processes necessary for insulin secretion and glucose homeostasis. The ultimate goal of the lab is to develop nutritional interventions that promote optimal function of pancreatic β cells predict and prevent the onset of diabetes. We will achieve this by developing molecular biology tools and cellular models of signaling pathways that regulate energy homeostasis.

Key Goals

  • Characterize molecular signaling regulated by novel G protein regulator of neurite outgrowth (Gprin), in pancreatic islets and in the brain.
  • Functional validation of novel islet GPCRs as targets involved in nutrients and metabolic sensing in the β-cells. Activation of these targets promotes pancreatic β-cell function and expansion.
  • Deliver scientific knowledge for Nestlé business innovation in personalized nutrition for pre-diabetics and patients with metabolic syndrome.
  • Taking into account molecular similarities between neurons and β-cell, expand the scope of research to neuronal signaling pathways that regulate.

 

Key Publications of the Group*

Kalwat MA, Huang Z, Wichaidit C, McGlynn K, Earnest S, Savoia C, Dioum EM, Schneider JW, Hutchison MR, Cobb MH. Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in β-Cells. ACS Chem. Biol. 2016.

Dioum E.M., Osborne J.K., Goetsch S., Russell, J., Schneider, J., Cobb, M.H.W. A small molecule differentiation inducer increases insulin production by pancreatic beta cell. PNAS, Vol. 108 (51) pp. 20713–20718, 2011.

Chen R, Dioum EM, Richard T. Hogg, Gerard Robert D, and Garcia JA. Hypoxia increases Sirtuin 1 expression in a Hypoxia Inducible Factor-dependent manner. J Biol Chem M110.175414, 2011.

Klein AM, Dioum EM, Cobb MH. Exposing contingency plans for kinase networks. Cell: 143 (6) 867-869, 2010.

Dioum EM, Wausson EM, and Cobb MH. MAP-ing unconventional protein-DNA interaction. Cell 139 (3): 462-463, 2009.

Dioum E.M, Chen R., Alexander M.S., Zhang Q., Hogg R.T., Gerard R.D., and Garcia J.A. Hypoxia Inducible Factor 2 alpha (HIF-2α) signaling during hypoxia is selectively regulated by Sirtuin 1. Science, 324(5932): 1289-93, 2009.

 

 

Stem Cells

Team Leader: Marine Kraus Ph.D. Contact

The aim of the Stem Cell group is to develop models of cellular and tissue systems involved in chronic diseases. The scientific approach is based on the creation of human cell-based models that take into account genetic and lifestyle differences between health and disease groups. Through an integrated systems approach, the stem cell group will focus on different functional metabolic states and molecular pathways relevant in metabolic, brain, aging and gastrointestinal health.

Key Goals

  • Discover potential new interventions and targets to improve cell function relevant for Metabolic Health, Cognitive Health and Ageing.
  • Gain key molecular insights into the control of cell differentiation.
  • Develop biological models by taking into account differences between patient groups and the genomic diversity of human beings.

 

Key Publications of the Group*

Eunyoung Choi, Marine R-C. Kraus, Laurence A. Lemaire, Momoko Yoshimoto, Sasidhar Vemula, Leah A. Potter, Elisabetta Manduchi, Christian J. Stoeckert Jr., Anne Grapin-Botton, Mark A. Magnuson.  Lineage-specific expression of Sox17 in specifying progenitor cell fate during mouse embryogenesis. Stem Cells, Oct 30, (10):2297-308, 2012.

Kraus MR and Grapin-Botton A. Patterning and shaping the endoderm in vivo and in culture. Curr Opin Genet Dev, Aug 22, (4):347-53, 2012.

Schwenter F., Zarei S., Luy P., Padrun V., Bouche N., Lee J.S., Mulligan R.C., Morel P., Mach N.  Cell encapsulation technology as a novel strategy for human anti-tumor immunotherapy. Cancer Gene Ther, Aug 18, (8): 553-62, 2011.

Baetge E.E. Production of beta-cells from human embryonic stem cells. Diabetes Obes. Metab. 10, Suppl 4: 186-194, 2008.

Kroon E., Martinson L.A., Kadoya K., Bang A.G., Kelly O.G., Eliazer S., Young H., Richardson M., Smart N.G., Cunningham J., Agulnick A.D., D'Amour K.A., Carpenter M.K., Baetge E.E.  Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol, 26 (4): 443-452, 2008.

McLean A.B., D'Amour K.A., Jones K.L., Krishnamoorthy M., Kulik M.J., Reynolds D.M., Sheppard A.M., Liu H., Xu Y., Baetge E.E., Dalton S. Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed. Stem Cells, 25 (1): 29-38, 2007.

 

*Some of these publications were done before the scientist/s joined the Nestlé Institute of Health Sciences