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 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 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 project(s):

• Metabolic regulation of mtDNA dependent inflammation. mtDNA can elicit inflammatory responses along the cGAS-STING pathway upon release from mitochondria into the cytosol. We recently showed that disturbances in the synthesis of nucleotides (for instance, upon treatment of cells with anti-cancer or anti-viral drugs or interfering with mitochondrial functions) can trigger mtDNA escape from mitochondria, linking inflammation to the cellular metabolism. Future experiments will investigate mechanisms of mtDNA release and the relevance of this pathway in ageing and disease.
• Proteostasis regulation in the intermembrane space of mitochondria. The mitochondrial disaggregase CLPB, associated with brain atrophy and movement disorders when mutated, and small heat shock proteins preserve proteostasis in the mitochondrial intermembrane space. However, their physiological roles and disease pathogenesis remains unclear and will be analyzed using tissue-specific knockout mouse models.
• The role of OMA1-DELE1-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. We found that the OMA1/DELE1-dependent stress response protects against ferroptosis and delays cardiomyopathy. The relative importance of mitochondrial stress signaling and regulation of mitochondrial morphology will be studied using mouse models for degenerative disorders.
• Reprogramming of mitochondria by the peptidase YME1L. Activation of the mitochondrial peptidase YME1L upon inhibition of mTORC1 triggers metabolic reprogramming of mitochondria, which facilitates the growth of pancreatic ductal adenocarcinoma 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 along the cGAS-STING pathway upon release from mitochondria into the cytosol. We recently showed that disturbances in the synthesis of nucleotides can trigger mtDNA escape from mitochondria, linking inflammation to the cellular metabolism. Future experiments will investigate mechanisms of mtDNA release and the relevance of this pathway in ageing and disease.

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 motivated and enthusiastic person with excellent basic knowledge in molecular and cell biology. Experience in mouse experimentation would be advantageous.

6. References:

1. 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 Reports42,112332. doi:10.1016/j.celrep.2023.112332.

2. 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. doi:10.1038/s41556-022-01071-y.

3. Adriaenssens, E., Asselbergh, B., Rivera-Mejías, P., Bervoets, S., Vendredy, L., De Winter, V., Spaas, K., de Rycke, R., van Isterdael, G., Impens, F., Langer, T. and Timmerman, V. (2023). Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space. Nat Cell Biol. 25, 467-480. doi:10.1038/s41556-022-01074-9.

4. 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. doi: 10.1016/j.cmet.2022.08.017.

5. 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.

6. Deshwal, S., Fiedler, K.U., Langer, T. (2020) Mitochondrial proteases – multi-faceted regulators of mitochondrial 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.