Prof. Dr. Thomas Langer

Research Area: Mitochondria, Proteostasis, Metabolism

Website: Langer Lab

1. Research Background:

Aging 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 aging but how perturbations in mitochondrial activities contribute to aging remains ill-defined. Organ failure during aging 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 aging. 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 opened up new research avenues, which significantly altered the view on the role of mitochondria for cell function. It became clear that mitochondria do not represent disparate entities in a cell. Rather, they communicate in many ways with their cellular environment resulting in changes of their proteome and shape in response to physiological demands and stress. Mitochondria thus serve as intracellular signaling platforms and regulators of age-related processes.

2. Research questions addressed by the group:

How is the functional integrity of mitochondria maintained during aging? How do mitochondria adapt to stress conditions and altered physiological demands during aging? 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 mitochondrial activities 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 with biochemical and quantitative 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:

  • Linking mitochondrial dynamics and stress signaling by OMA1. 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 OMA1 activation and increased OPA1 processing is associated with heart failure and leads to cell-type specific axonal degeneration. However, it remained speculative whether altered OPA1 processing and mitochondrial fragmentation or impaired stress signalling and altered metabolic functions of OMA1 cause these deficiencies. Using various available knockout mouse lines which were generated by CRISPR/Cas9 genome editing and which allow to uncouple the various functions of OMA1, we will analyse the role of OPA1- and DELE1 processing in mitochondrial disease and ageing, which should also provide insight into the question why mitochondrial form and function need to be coupled.
  • OMA1-mediated metabolic rewiring of mitochondria under DNA damage. Whereas stress-induced OPA1 processing by OMA1 promotes apoptosis, 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 ductal adenocarcinoma cells and neuronal 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 disturbances in the synthesis of nucleotides (by interfering with nucleotide synthesis or uptake of nucleotides into mitochondria or upon treatment of cells with anti-cancer or anti-viral drugs) can trigger mtDNA escape from mitochondria, linking the cellular metabolism to inflammation. 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 cellular biology. Experience in mouse experimentation would be advantageous but is not a prerequisite.

6. References:

  1. 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.
  2. Bahat, A., MacVicar, T., Langer, T. (2021). Metabolism and innate immunity meet at the mitochondria. Front. Cell Dev.Biol. 9, 720490.
  3. Nolte, H. and Langer, T. (2021). ComplexFinder: A software package for the analysis of native protein complex fractionation experiments. BBA – Bioenergetics 1862, 148444.
  4. Deshwal, S., Fiedler, K.U., Langer, T. (2020) Mitochondrial proteases – multi-faceted regulators of mitochondrial plasticity. Annu. Rev. Biochem., 89, 501-528.
  5. 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. Nature575(7782), 361–365.
  6. Sprenger, H.S., Wani, G., Hesseling, A., König, T., Patron, M., MacVicar, T., Ahola, S., Wai, T., Barth, E., Rugarli, E.I., Bergami, M. and Langer, T. (2019) Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol. Medicine 11: e9288.
  7. 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.