Universität zu Köln 

Prof. Dr. Thomas Langer

Institut für Genetik/CECAD Forschungszentrum,
Universität zu Köln
email: Thomas.Langer(at)uni-koeln.de
phone: +49-(0)221 478 84263
website

The biogenesis of mitochondria is under proteolytic control of two AAA proteases, ATP-dependent proteases in the inner membrane that are built up of conserved subunits. While the i-AAA protease exposes proteolytic and ATPase domains to the intermembrane space of mitochondria, the m-AAA protease is active on the matrix side. Mutations in subunits of the m-AAA protease have been associated with various neurodegenerative disorders. Our findings have established versatile activities of AAA proteases in mitochondria: they conduct protein quality control surveillance, act as processing enzymes, and mediate the ATP-dependent membrane dislocation of specific proteins. The processing of the ribosomal subunit MrpL32 by the m-AAA protease was identified as a central regulatory function of the m-AAA protease, which controls mitochondrial ribosome assembly and protein synthesis. Recent experiments identified the i-AAA protease as part of a conserved regulatory network in the intermembrane space, which controls the accumulation of phosphatidyl ethanolamine and cardiolipin in mitochondrial membranes. Moreover, genome-wide synthetic genetic arrays linked the function of both AAA proteases to the mitochondrial phospholipid metabolism which will be examined in detail in the next funding period. We will use a mutant variant of the m-AAA protease which allows distinguishing its functions in phospholipid metabolism and ribosome assembly. Quantitative mass spectrometry after affinity purification of AAA protease complexes will be performed to identify novel substrates of both m-AAA and i-AAA proteases. Another focus of research will be to examine determinants of substrate recognition by AAA proteases. The identification of specific substrates of both AAA proteases allows us to define specific degrons in substrate proteins that are recognised by substrate binding regions at the surface of AAA protease complexes, to examine the role of N-terminal amino acid residues for the stability of mitochondrial proteins, and to define the function of putative substrate adaptor proteins.

These studies will further define regulatory functions of AAA proteases for mitochondrial biogenesis which are likely to be of direct relevance for functionally conserved mammalian orthologues and, therefore, for our understanding of neurodegenerative disorders associated with mutations in AAA protease subunits.

Running time: 07/2003 – 06/2015

Recent publications:

Almontashiri, N.A.M., Chen, H.-H., Mailloux, R.J., Tatsuta, T., Teng, A.C.T., Mahmoud, A.B., Ho, T., Stewart, N.A.S., Rippstein, P., Harper, M.E., Roberts, R., Willenborg, C. and Erdmann, J. for the CARDIoGRAM Consortium, Pastore, A., McBride, H.M., Langer, T., and Stewart, A.F.R. (2014). SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. Cell Rep. 7, 834-47. PubMed

Kondadi, A.K., Wang, S., Montagner, S., Kladt, N., Korwitz, A., Martinelli, P., Herholz, D., Baker, M.J., Schauss, A.C., Langer, T., and Rugarli, E.I. (2014). Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation. EMBO J. 33, 1011-1026. PubMed

Almajan, E.R., Richter, R., Paeger, L., Martinelli, P., Barth, E., Decker, T., Larsson, N.G., Kloppenburg, P., Langer, T., and Rugarli, E.I. (2012). AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. J. Clin. Invest., in press.

Rugarli E.I. and Langer, T. (2012). Mitochondrial quality control – a matter of life and death for neurons. EMBO J. 31, 1336-1349.

Anand, R., Langer, T., and Baker, M. (2012). Proteolytic control of mitochondrial function and morphogenesis. BBA -. Mol. Cell Res., doi: 10.1016/j.bbamcr.2012.05025

Pierson, T.M., Adams, D., Bonn, F., Martinelli, P., Cherukuri, P.F., Teer, J.K., Hansen, N.F., Cruz, P., Mullikin For The Nisc Comparative Sequencing Program, J.C., Blakesley, R.W., Golas, G., Kwan, J., Sandler, A., Fuentes Fajardo, K., Markello, T., Tifft, C., Blackstone, C., Rugarli, E.I., Langer, T., Gahl, W.A., and Toro, C. (2011). Whole-Exome Sequencing Identifies Homozygous AFG3L2 Mutations in a Spastic Ataxia-Neuropathy Syndrome Linked to Mitochondrial m-AAA Proteases. PLoS Genet 7(10):e1002325. Epub 2011 Oct 13.

Bonn, F., Tatsuta, T., Petrungaro, C., Riemer, J., and Langer, T. (2011). Presequence-dependent folding ensures MrpL32 processing by the m-AAA protease in mitochondria. EMBO J., 30, 2545-2556.

Lee, S., Augustin, S., Tatsuta, T., Gerdes, F., Langer, T., and Tsai, F.T. (2011). Electron cryomicroscopy structure of a membrane-anchored mitochondrial AAA protease. J. Biol. Chem. 286, 4404-4411.

Gerdes, F., Tatsuta, T., and Langer, T. (2011). Mitochondrial AAA proteases - Towards a molecular understanding of membrane-bound proteolytic machines. Biochim. Biophys. Acta 1823, 49-55.

Baker, M., Tatsuta, T., and Langer, T. (2011). Quality control of mitochondrial proteostasis. CSH Perspect Biol., 3, 7-14.

Lee, S., Augustin, S., Tatsuta, T., Gerdes, F., Langer, T., and Tsai, F.T. (2010). Electron cryomicroscopy structure of a membrane-anchored mitochondrial AAA protease. J. Biol. Chem. 286, 4404-11.

Potting, C., Wilmes, C., Engmann, T., Osman, C., and Langer, T. (2010). Regulation of mitochondrial phospholipids by Ups1/PRELI-like proteins depends on proteolysis and Mdm35. EMBO J. 29, 2888-2898.