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B06 | Role of mitochondrial outer membrane permeabilisation in mitochondrial hepatopathy

Hamid Kashkar
CECAD Research Center/Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University Hospital Cologne

E-mail: H.KashkarSpamProtectionuni-koeln.de
Phone: +49 - 221 / 478 84091
For more information and contact please visit the KASHKAR LAB.


Running time within the CRC 1218: 07/2016 - 06/2024.

Abstract

Mitochondrial respiratory dysfunction in liver causes mitochondrial hepatopathy which leads to premature lethality. This project investigates the role of mitochondrial outer membrane permeabilisation (MOMP) during the course of disease pathogenesis and examines whether therapeutic interventions aiming at inducing MOMP can block disease manifestation.

Project-related publications

Schiffmann, L.M., Werthenbach, J. P., Heintges-Kleinhofer, F., Seeger, J.M., Fritsch, M., Günther, S. D. Willenborg, S., Brodesser, S. [1], Lucas, C., Jüngst, C., Albert, M. C., Schorn, F., Witt, A., Moraes, C. T., Bruns, C. J., Pasparakis, M., Krönke, M., Eming, S. A., Coutelle, O., and Kashkar, H. (2020). . Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. Nat. Commun. 11, 3653 (2020).

Fritsch, M., Günther, S.D., Schwarzer, R., Albert, M.C., Schorn, F., Werthenbach, J.P., Schiffmann, L.M., Stair, N., Stocks, H., Seeger, J.M., Lamkanfi, M., Krönke, M., Pasparakis, M., and Kashkar, H. (2019). Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 575, 683-687.

Gräb, J., Suarez, I., van Gumpel, E., Winter, S., Schreiber, F., Esser, A., Hölscher, C., Fritsch, M., Herb, M., Schramm, M., Wachsmuth, L., Pallasch, C., Pasparakis, M., Kashkar, H., and Rybniker, J. (2019). Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition. Nat. Commun. 10, 688.

Günther, S.D., Fritsch, M., Seeger, J.M., Schiffmann, L.M., Snipas, S.J., Coutelle, M., Kufer, T.A., Higgins, P.G., Hornung, V., Bernardini, M.L., Höning, S., Krönke, M., Salvesen, G.S., and Kashkar, H. (2019). Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through LPS. Nat. Microbiol., Epub ahead of print. DOI 10.1038/s41564-019-0620-5.

Habich, M., Salscheider, S.L., Murschall, L.M., Hoehne, M.N., Fischer, M., Schorn, F., Petrungaro, C., Ali, M., Erdogan, A.J., Abou-Eid, S., Kashkar, H., Dengjel, J., and Riemer, J. (2019). Vectorial import via a metastable disulfide-linked complex allows for a quality control step and import by the mitochondrial disulfide relay. Cell Rep. 26, 759-774.

Holzer, T., Probst, K., Etich, J., Auler, M., Georgieva, V., Bluhm, B., Frie, C., Heilig, J., Niehoff, A., Nüchel, J., Plomann, M., Seeger, J.M., Kashkar, H., Baris, O.R., Wiesner, R.J., and Brachvogel, B. (2019). Respiratory chain inactivation links cartilage-mediated growth retardation to mitochondrial diseases. J. Cell Biol. 218, 1853-1870

Schiffmann, L.M., Fritsch, M., Gebauer, F., Günther, S.D., Stair, N.R., Seeger, J.M., Thangarajah, F., Dieplinger, G., Bludau, M., Alakus, H., Göbel, H., Quaas, A., Zander, T., Hilberg, F., Bruns, C.J., Kashkar, H., and Coutelle, O. (2019). Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br. J. Cancer 120, 69-78.

Chauhan, D., Bartok, E., Gaidt, M.M., Bock, F.J., Herrmann, J., Seeger, J.M., Broz, P., Beckmann, R., Kashkar, H., Tait, S.W.G., Müller, R., and Hornung, V. (2018). BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages. Cell Rep. 25, 2354-2368.

Saita, S., Nolte, H., Fiedler, K.U., Kashkar, H., Venne, A.S., Zahedi, R.P., Krüger, M., and Langer, T. (2017). PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis. Nat Cell Biol. 19, 318-328.

Schiffmann, L.M., Brunold, M., Liwschitz, M., Goede, V., Loges, S., Wroblewski, M., Quaas, A., Alakus, H., Stippel, D., Bruns, C.J., Hallek, M., Kashkar, H., Hacker, U.T., Coutelle, O. (2017). A combination of low-dose bevacizumab and imatinib enhances vascular normalisation without inducing extracellular matrix deposition. Br. J. Cancer. 116, 600-608.

Knittel, G., Liedgens, P., Korovkina, D., Seeger, J. M., Al-Baldawi, Y., Al-Maarri, M., Fritz, C., Vlantis, K., Bezhanova, S., Scheel, A. H., Wolz, O. O., Reimann, M., Möller, P., López, C., Schlesner, M., Lohneis, P., Weber, A. N., Trümper, L., German International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing Project Consortium, Staudt, L. M., Ortmann, M., Pasparakis, M., Siebert, R., Schmitt, C. A., Klatt, A. R., Wunderlich, F. T., Schäfer, S. C., Persigehl, T., Montesinos-Rongen, M., Odenthal, M., Büttner, R., Frenzel, L. P., Kashkar, H., Reinhardt, H. C. (2016). B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice. Blood 127, 2732-41.

Schüll, S., Günther, S.D., Brodesser, S., Seeger, J.M., Tosetti, B., Wiegmann, K., Pongratz, C., Diaz, F., Witt, A., Andree, M., Brinkmann, K., Krönke, M., Wiesner, R.J., and Kashkar, H. (2015). Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6. Cell Death Dis. 6, e1691.