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 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 aging and age-related disease.

2. Research questions addressed by the group:

How is the functional integrity of mitochondria maintained during aging? How do mitochondria adapt to stress and altered physiological demands? How do metabolic disturbances of mitochondria affect innate immune signaling and inflammatory responses? How does an altered mitochondrial form and function 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 and analyze consequences if these mechanisms go awry in ageing and disease. 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 and quantitative proteomic and metabolomic approaches, we have identified key roles of mitochondrial proteases for the regulation of mitochondrial metabolism, dynamics, protein biogenesis, lipid trafficking, cellular calcium and stress 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. Selected possible project(s):

• Spatial organization of proteolysis by prohibitin membrane scaffolds. Prohibitins are essential for mitochondrial functions and have been linked to inflammation, ageing and various diseases. We are interested in defining the composition and regulation of membrane domains formed by prohibitin ring complexes as proteolytic hubs in the mitochondrial inner membrane, using chemical crosslinking combined with mass spectrometry and structural modelling.
• Proteolytic control of mitochondrial protein import. The mitochondrial adaptation to stress involves the reshaping of mitochondrial protein translocase complexes by proteolysis (Kroczek et al., 2026; Kroczek and Langer, 2026), which limits the accumulation of OXPHOS-related proteins in mitochondria. However, the different stability of protein translocase subunits affects protein import specificity remained unclear. Moreover, the accumulation of non-imported mitochondrial preproteins at the endoplasmic reticulum elicits an unfolded protein response, highlighted the importance of inter-organellar communication under stress conditions, which will be further studied.
• Metabolic regulation of mtDNA dependent inflammation (Sprenger et al., 2021; Bahat et al., 2025). An imbalanced nucleotide metabolism leads to the release of mtDNA from mitochondria to the cytosol, where it elicits an inflammatory response along the cGAS-STING pathway, linking inflammation to the cellular metabolism. Future experiments will investigate mechanisms of mtDNA release and the relevance of this pathway in senescence and ageing.

4. Applied Methods and model organisms:

The group combines ´state-of-the-art` biochemical, live cell imaging, and genome editing techniques with quantitative proteomics 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 motivated and enthusiastic person with excellent basic knowledge in molecular and cell biology. Experience in the use of biochemical approaches and/or mouse experimentation would be advantageous.

6. References:

Kroczek, L., H. Nolte, Y. Lasarzewski, I. Agrawal, T. Molinie, D. Curbelo Pinero, K. Lemke, E. Rugarli, and T. Langer. 2026. Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15. Nat Struct Mol Biol. 33:499-511.

Kroczek, L., and T. Langer. 2026. Proteolytic control of mitochondrial protein translocases. Protein Sci. 35:e70553.

Bahat, A., Milenkovic, D., Cors, E., Barnett, M., Niftullayev, S., Katsalifis, A., Schwill, M., Kirschner, P., MacVicar, T., Giavalisco, P., Jenninger, L., Clausen, A.R., Paupe, V., Prudent, J., Larsson N.-G., Rogg, M., Schell, C., Muylaert, I., Lekholm, E., Nolte, H., Falkenberg, M., Langer, T. (2025). Ribonucleotide incorporation into mitochondrial DNA drives inflammation. Nature, 647, 726-734.

Yamada, T., Ikeda, A., Murata, D., Zhang, C., Khare, P., Adachi, Y., Ito, F., Quirós, P.M., López-Otín, C., Langer, T., Chan, D.C., Dawson., T.M., Le., A., Iijima, M., Sesaki, H. (2025). Dual Regulation of Mitochondrial Fusion by Parkin-PINK1 and Oma1. Nature, 639, 776-783. 

Ahola, S., Pazurek, L., Mayer, F., Lampe, P., Hermans, S., Becker, L., Amarie, O.V., Fuchs, H., Gailus-Durner, V., Hrabe de Angelis, M., Riedel, D., Nolte, H. and Langer, T. (2024). Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy. Sci. Advances 10, eadp0443.

Rivera Meijias, P., Narbona-Perez, A.J., Hasberg, L., Kroczek, L., Bahat, A., Lawo S., Folz-Donahue, K., Schumacher, A.-L., Ahola, S., Mayer, FC., Giavalisco, P., Nolte, H., Lavandero, S. and Langer, T. (2023). The mitochondrial protease OMA1 acts as metabolic safeguard upon nuclear DNA damage. Cell Reports 42,112332.

Deshwal, S., Onishi, M., Tatsuta, T., Bartsch, T., Cors, E., Ried, K., Lemke, K., Nolte, H., Giavalisco, P. and Langer, T. (2023). Mitochondria regulate intercellular coenzyme Q transport and ferroptotic resistance via STARD7. Nat Cell Biol. 25, 246-257.

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., 34(11), 1875-1891.

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.

Deshwal, S., Fiedler, K.U., Langer, T. (2020) Mitochondrial proteases – multi-faceted regulators of mitochondrial plasticity. Annu. Rev. Biochem., 89, 501-528.