Prof. Dr. Thomas Langer

Research Area: Mitochondria, Proteostasis, Metabolism

Branches: BiochemistryCell Biology

Website: Langer Lab

Prof. Dr. Thomas Langer

1. Research Background:

Ageing is defined by a decline in the functional capacity of cells, organs and organisms. Mitochondria are intimately linked to a wide range of processes associated with ageing but how perturbations in mitochondrial activities contribute to ageing remains ill-defined. Organ failure during ageing is accompanied by a decline in the bioenergetic capacity of mitochondria and the accumulation of aberrant mitochondria, raising the possibility that mitochondrial dysfunction causally contributes to ageing. The devastating consequences of impaired mitochondrial activities are illustrated by numerous inherited brain and muscle diseases that are associated with mutations affecting mitochondrial proteins. Since mitochondria are the primary site of cellular energy production and perform vital biosynthetic functions, mitochondrial research has been focused for decades on oxidative phosphorylation and the biogenesis of the organelle. However, the notion that mitochondria are highly plastic and dynamic organelles that constantly fuse and divide and adapt their proteome opened up new research avenues, which significantly altered the view on the role of mitochondria for cell function. Understanding the dynamic and plastic behavior of the mitochondrial proteome is mandatory to understand their role in ageing and age-related disease.

2. Research questions addressed by the group:

How is the functional integrity of mitochondria maintained during ageing? How do mitochondria adapt to stress conditions and altered physiological demands? How does an altered mitochondrial form and function in disease cause tissue-specific disease and limit lifespan? These are central research questions of our group. It is our working hypothesis that decreased mitochondrial plasticity and an impaired ability of mitochondria to adjust their function limit lifespan and cause age- associated diseases. We are studying mechanisms that drive the functional plasticity of mitochondria and allow adapting their form and metabolic function. Mitochondrial proteases are emerging as central regulators of these processes that shape the mitochondrial proteome, determine the structure and function of mitochondria and regulate mitochondrial signaling in response to physiological cues. Proteolytic activities decline with age and numerous inherited diseases are associated with mutations in mitochondrial proteases, highlighting their central relevance for the functional integrity of mitochondria.

Combining mouse genetic approaches and CRISPR screens in cultured cells with biochemical andquantitative proteomic and metabolomic approaches, we have identified key roles of mitochondrial proteases for the regulation of mitochondrial metabolism, dynamics, cell death, lipid trafficking, cellular calcium signalling and inflammatory responses. These discoveries revealed new regulatory principles and are of fundamental importance for our understanding of age-related pathologies that are associated with mitochondrial deficiencies.

3. Possible projects:

  • The protective role of OMA1-dependent stress responses against ferroptosis in degenerative disorders. The stress-activated mitochondrial peptidase OMA1 regulates mitochondrial dynamics via processing of the dynamin-like GTPase OPA1, while eliciting a mitochondrial stress response via processing of DELE1. Using tissue-specific knockout mouse models, we found that mitochondrial dysfunction in the heart activates OMA1, which cleaves DELE1 and elicits an integrated stress response. The OMA1/DELE1-dependent stress response protects againstferroptosis and delays cardiomyopathy. Further experiments using available knockout mouse lines aim at defining how the stress response limits ferroptosis and at examining a possible protective effect of the OMA1/DELE1-dependent stress response in neurodegenerative disorders.
  • OMA1-mediated metabolic rewiring of mitochondria under DNA damage. We found that metabolic reprogramming of mitochondria by OMA1 is required for the survival of proliferating cells upon DNA damage. Further experiments aim at defining this novel pro-survival role of OMA1 and its relevance in the context of different cancers.
  • Reprogramming of mitochondria by the peptidase YME1L. Activation of the mitochondrial peptidase YME1L upon inhibition of mTORC1 in starved and hypoxic cells triggers metabolic reprogramming of mitochondria, which facilitates the growth of pancreatic ductaladenocarcinoma cells and neural stem cells in vivo. Future experiments will define how YME1L regulates mitochondrial function and assess the role of the mTORC1/YME1L axis for longevity, during stem cell differentiation and in various (patho-)physiological conditions.
  • Metabolic regulation of mtDNA dependent inflammation. mtDNA can elicit inflammatory responses upon release from mitochondria into the cytosol. Our recent studies indicated that the loss of the mitochondrial peptidase YME1L and/or disturbances in the synthesis of nucleotides (for instance, upon treatment of cells with anti-cancer or anti-viral drugs) can trigger mtDNA escape from mitochondria, linking inflammation to the cellular metabolism. Future experiments will investigate the effect of nucleotide imbalances on mtDNA, possible mechanisms of mtDNA release and the role of novel YME1L substrates and components involved in the cellular nucleotide metabolism.

4. Applied Methods and model organisms:

The group combines ´state-of-the-art` biochemical, live cell imaging, and genome editing techniques with quantitative proteomics and metabolomics by mass spectroscopy. We are using genetically modified mice as well as genetically engineered cell lines and cultured primary cells as models.

5. Desirable skills and qualifications:

We are looking for a highly motivated and enthusiastic person with excellent basic knowledge in molecular and cell biology. Experience in mouse experimentation would be advantageous but is not a prerequisite.

6. References:

  1. Ahola, S., Rivera Mejias, P., Hermans, S., Chandragiri S., Giavalisco, P., Nolte, H., and Langer T. (2022).OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. Cell Metab., in press.
  2. Patron, M., Tarasenko, D., Nolte, H., Kroczek, L., Ghosh, M., Ohba, Y., Lasarzewski, Y., Ahmadi, Z.A.,Cabrera-Orefice, A., Eyiama, A., Kellermann, T., Rugarli, E.I., Brandt, U., Meinecke, M., and Langer, T. (2022). Regulation of mitochondrial proteostasis by the proton gradient. EMBO J., in press.
  3. 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. and Bergami, M. (2022). Metabolic contrl of adult neural stem cell self-renewal by the mitochondrial protease YME1L. Cell Rep. 38, 110370.
  4. Sprenger, H.G., MacVicar, T., Bahat, A., Fiedler, K.U., Hermans, S., Ehrentraut, D., Ried, K., Milenkovic,D., Bonekamp, N., Larsson, N.G., Nolte, H., Giavalisco, P. and Langer, T. (2021). Cellular pyrimidine   imbalance triggers mitochondrial DNA- dependent innate immunity. Nat. Metabol. 3, 636-650.
  5. Nolte, H. and Langer, T. (2021). ComplexFinder: A software package for the analysis of native proteincomplex fractionation experiments. BBA – Bioenergetics 1862, 148444.
  6. Deshwal, S., Fiedler, K.U., Langer, T. (2020) Mitochondrial proteases – multi- faceted regulators ofmitochondrial plasticity. Annu. Rev. Biochem., 89, 501-528.
  7. MacVicar, T., Ohba, Y., Nolte, H., Mayer, FC., Tatsuta, T., Sprenger, HG., Lindner, B., Zhao, Y., Li, J., Bruns, C., Krüger, M., Habich, M., Riemer, J., Scharzer, R., Pasparakis, M., Henschke, S., Brüning, JC., Zamboni, N. and Langer, T. (2019) Lipid signalling drives proteolytic rewiring of mitochondria by YME1L. Nature 575(7782), 361–365.