Department of Cell Biology

Thomas Simmen


Thomas Simmen

Ph.D., University of Lausanne

Professor
Office: 780-492-1546
thomas.simmen@ualberta.ca

Research

Membrane Contact Sites between the endoplasmic reticulum (ER) and mitochondria as determinants in cancer and neurodegeneration

Current biomedical research aims to understand how we can pharmacologically halt the progression of a variety of chronic diseases that are associated with aging or genetic mutations. Prominent examples are cancer and neurodegeneration, where the cellular lifespan is either abnormally extended (cancer) or shortened (neurodegeneration). Other examples include muscular dystrophy and diabetes. Frequently, it is thought that a major cause for such diseases lies in the alteration of cellular metabolism that would compromise the proper functioning and survival of cells.

Our laboratory works to understand how such changes occur and how we can manipulate them. To do so, we focus on intracellular contact sites between two organelles: the endoplasmic reticulum (ER) and mitochondria. On these contact sites, the two organelles exchange Ca2+ ions. This ion flux controls the progression of the Krebs cycle inside mitochondria and can trigger the release of pro-apoptotic proteins from mitochondria. Therefore, the extent by which the ER and mitochondria interact with each other determines cellular energy production and cellular death.

In multiple publications from the lab, we have shown that when contacts between the ER and mitochondria are not formed properly, imbalances of cellular metabolism and abnormal cellular lifespan result. We have detected the same changes in specimens from human patients that suffer from cancer and multiple sclerosis (MS). In ongoing research, we now characterize further mechanisms associated with defects of ER-mitochondria contacts and how they malfunction in disease.

Candidates for undergraduate research (Cell 398, 498, 499), for summer studentships, for graduate studies or for postdoctoral fellowships are invited to contact the Principal Investigator at thomas.simmen@ualberta.ca

 

 Simmen Research Pic 1

Measuring the extent of ER-Mitochondria contact formation via electron microscopy. The knockdown of the TMX1 protein reduces contacts (see reference 2 Raturi et al., 2016).


Selected Publications

1. Haile, Y., Deng, X., Ortiz-Sandoval, C., Tahbaz, N., Janowicz, A., Lu, J. Q., Kerr, B. J., Gutowski, N. J., Holley, J. E., Eggleton, P., Giuliani, F., Simmen, T. (2017) Rab32 connects ER stress to mitochondrial defects in multiple sclerosis. Journal of Neuroinflammation. 23;14(1):19.

2. Raturi, A., Gutiérrez, T., Ortiz-Sandoval, C., Ruangkittisakul, A., Herrera-Cruz, M. S., Rockley, J. P., Gesson, K., Ourdev, D., Lou, P. H., Lucchinetti, E., Tahbaz, N., Zaugg, M., Baksh, S., Ballanyi, K., and Simmen, T. (2016) TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux. Journal of Cell Biology. 214(4):433-44.

3. Arasaki, K., Shimizu, H., Mogari, H., Nishida, N., Hirota, N., Furuno, A., Kudo, Y., Baba, M., Baba, N., Cheng, J., Fujimoto, T., Ishihara, N., Ortiz-Sandoval, C., Raturi, A., Barlow, L., Dohmae, N., Wakana, Y., Inoue, H., Tani, K., Dacks, J.B., Simmen, T. & Tagaya, M. (2015) A novel role for the ancient SNARE Syntaxin 17 in regulating mitochondrial division. Developmental Cell. 32(3):304-17.

4. Lynes, E.M., Raturi, A., Shenkman, M., Ortiz Sandoval, C., Yap, M.C., Janowicz, A., Myhill, N., Benson, M.D., Berthiaume, L.G., Lederkremer, G.Z., and Simmen, T. (2013) Palmitoylation is the Switch that Assigns Calnexin to Quality Control or ER Calcium Signaling. Journal of Cell Science. Sep 1;126(Pt 17):3893-903.

5. Lynes E. M., Bui M., Yap M. C., Benson M. D., Schneider B., Ellgaard L., Berthiaume L. G., and Simmen T. (2012) Palmitoylated TMX and calnexin target to the mitochondria-associated membrane. EMBO Journal. 31(2):457-70.

6. Bravo, R., Vicencio, J.M., Parra, V., Troncoso, R., Munoz, J.P., Bui, M., Quiroga, C., Rodriguez, A.E., Verdejo, H.E., Ferreira, J., Iglewski, M., Chiong, M., Simmen, T., Zorzano, A., Hill, J.A., Rothermel, B.A., Szabadkai, G., and Lavandero, S. (2011) Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. Journal of Cell Science, Jul 1;124(Pt 13):2143-52.

7. Bui, M., Gilady, S.Y., Fitzsimmons, R.E.B., Benson, M.D., Lynes, E.M., Gesson, K., Alto, N.M., Strack, S., Scott, J.D., and Simmen, T. (2010) Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties. Journal of Biological Chemistry, 285(41):31590-602.

8. Myhill, N., Lynes, E.M., Nanji, J.A., Blagoveshchenskaya, A.D., Fei, H., Carmine Simmen, K., Cooper, T.J., Thomas, G., and Simmen, T. (2008) The Subcellular Distribution of Calnexin Is Mediated by PACS-2. Molecular Biology of the Cell, 19(7), 2777-88.