A01 | Proteolytic control of mitochondrial dynamics and metabolism by OMA1
Thomas Langer
Max Planck Institute for Biology of Ageing,
Cologne
E-mail: tlanger
age.mpg.de
For more information and contact please visit the LANGER LAB.
Running time within the CRC 1218: 07/2016 - 06/2024.
Abstract
The project aims to define the role of the stress-activated peptidase OMA1 in the regulation of mitochondrial dynamics and function in response to stress and different metabolic demands. The project combines multiple proteomic approaches and experiments in cultured cells with in vivo approaches in mouse to unravel how OMA1 regulates the stress response of mitochondria and cell survival and to uncover novel functions of OMA1 within mitochondria.
Project-related publications
Peker, E., Weiss, K., Song, J., Zarges, C., Gerlich, S., Boehm, V., Trifunovic, A., Langer, T., Gehring, N., Becker, T. and Riemer, J. (2023). A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis. J. Cell Biol. 222, e202210019.
Montoro-Gámez, C., Nolte, H., Molinié, T., Evangelista, G., Tröder, S., Barth, E., Popovic, M., Trifunovic, A., Zevnik, B., Langer, T., Rugarli E.I. SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency. Brain. 2023 Apr 22:awad136. doi: 10.1093/brain/awad136. Online ahead of print. PMID: 37086482
Ahola, M., Rivera, M. P., Hermans, S., Chandragiri, S., Giavalisco, P., Nolte, H., Langer, T. (2022). OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. Cell Metab. 2022 Sep 8;S1550-4131(22)00360-6. doi: 10.1016/j.cmet.2022.08.017.
Patron, M., Tarasenko, D., Nolte, H., Ghosh, M., Ohba, Y., Lasarzewski, Y., Ahmadi, Z.A., Cabrera-Orefice, A., Eyiama, A., Kellermann, T., Rugarli, E.I., Brandt, U., Meinecke, M., Langer, T. (2022). Regulation of mitochondrial proteostasis by the proton gradient. The EMBO Journal (2022)e110476. https://doi.org/10.15252/embj.2021110476
Schatton, D., Di Pietro, G., Szczepanowska, K., Veronese, M., Marx, M.-C., Braunöhler, K., Esther, B., Müller, S., Giavalisco, P., Langer, T., Trifunovic, A., Rugarli, I.E. (2022). CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression. Elife. 2022 May 13;11:e74552. DOI: 10.7554/eLife.74552
Wani, G.A., Sprenger, H.-G., Ndoci, K., Chandragiri, S., Acton, R.J., Schatton, D., Kochan, S.M.V., Sakthivelu, V., Jevtic, M., Seeger, J.M., Müller, S., Giavalisco, P., Rugarli, E.I., Motori, E., Langer, T., Bergami, M. (2022). Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L. Cell Reports • DOI:https://doi.org/10.1016/j.celrep.2022.110370
Willenborg, S., Sanin, D.E., Jais, A., Ding, X., Ulas, T., Nüchel, J., Popović, M., MacVicar, T., Langer, T., Schultze, J.L., Gerbaulet, A., Roers, A., Pearce, E.J., Brüning, J.C., Trifunovic, A., Eming, S.A. (2021). Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metabolism (2021), https://doi.org/10.1016/j.cmet.2021.10.004
Murschall, L,M*., Peker, E*., MacVicar, T., Langer, T., Riemer, J. (2021). Protein Import Assay into Mitochondria Isolated from Human Cells. Bio-protocol 11 (12), e4057-e4057
Aravamudhan, S., Türk, C., Bock, T., Keufgens, L., Nolte, H., Lang, F., Krishnan, R.K., König, T., Hammerschmidt, P., Schindler, N., Brodesser, S., Rozsivalova, D.H., Rugarli, E., Trifunovic, A., Brüning, J., Langer, T., Braun, T., Krüger, M. (2021). Phosphoproteomics of the developing heart identifies PERM1 - An outer mitochondrial membrane protein. 2021 Feb 5;154:41-59. doi.org/10.1016/j.yjmcc.2021.01.010
Murschall, L.M., Gerhards, A., MacVicar, T., Peker, E., Hasberg, L., Wawra, S., Langer, T., Riemer, J. (2020). The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import.
DOI: 10.1186/s12915-020-00824-1
Deshwal, S., Fiedler, K.U., and Langer, T. (2020). Mitochondrial Proteases: Multifaceted Regulators of Mitochondrial Plasticity. Annu. Rev. Biochem., doi: 10.1146/annurev-biochem-062917-012739. [Epub ahead of print]
MacVicar, T., Ohba, Y., Nolte, H., Mayer, F., Tatsuta, T., Sprenger, H.G., Lindner, B., Zhao, Y., Li, J., Bruns, C., Krüger, M., Habich, M., Riemer, J., Schwarzer, R., Pasparakis, M., Henschke, S., Brüning, J., Zamboni, N. and Langer, T. (2019). Lipid signalling drives proteolytic rewiring of mitochondria by YME1L. Nature 575 , 361-365.
Murru, S., Hess, S., Barth, E., Almajan, E.R., Schatton, D., Hermans, S., Brodesser, S., Langer, T., Kloppenburg, P., Rugarli, E.I. (2019). Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration. GLIA 67, 1526-1541.
Sprenger, H.G. and Langer, T. (2019). The good and the bad of mitochondrial breakups. Trends Cell Biol. 29, 888-900. doi: 10.1016/j.tcb.2019.08.003. [Epub ahead of print].
Richter, F., Dennerlein, S., Nikolov, M., Jans, D., Naumenko, N., Aich, A., MacVicar, T., Linden, A., Jakobs, S., Urlaub, H., Langer, T. and Rehling, P. (2019). ROMO1 is a constituent of the human presequence translocase required for YME1L protease import. J. Cell Biol. 218, 598-614.
Sprenger, H.G., Wani, G., Hesseling, A., König, T., Patron, M., MacVicar, T., Ahola, S., Wai, T., Barth, E., Rugarli, E.I., Bergami, M., Langer, T. (2018). Loss of the mitochondrial i‐AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol Med. pii: e9288. doi: 10.15252/emmm.201809288. [Epub ahead of print]
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.
MacVicar, T. and Langer, T. (2016). OPA1 processing in cell death and disease: the long and short of it. J. Cell Sci. 129, 2297-2306.
Korwitz, A., Merkwirth, C., Richter-Dennerlein, R., Tröder, S.E., Sprenger, H.-G., Quiros, P.M., López-Otín, C., Rugarli, E.I., and Langer, T. (2016). Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria. J. Cell Biol. 212, 157-166.
Wang, S., Jacquemyn, J., Murru, S., Martinelli, P., Barth, E., Langer, T., Niessen, C.M., and Rugarli, E.I. (2016). The mitochondrial m-AAA protease prevents demyelination and hair greying. PLoS Genet 12, e1006463.
Wai, T., García-Prieto, J., Baker, M.J., Merkwirth, C., Benit, P., Rustin, P., Rupérez, F.J., Barbas, C., Ibañez, B.*, and Langer, T.* (2015). Imbalanced OPA1 processing and mitochondrial fragmentation causes heart failure in mice. Science 350, 1221-1233. *shared senior authorship.
Baker, M.J., Lampe, P.A., Stojanovski, D., Korwitz, A., Anand, R., Tatsuta, T., and Langer, T. (2014). Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics. EMBO J. 33, 578-593.
Anand, R., Wai, T., Baker, M.J., Kladt, N., Schauss, A.C., Rugarli, E.I., and Langer, T. (2014). The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J. Cell Biol. 204, 919-929.