Research Area: Mitochondrial biology, Metabolism, Inflammation
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. 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 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 dynamics, apoptosis, phospholipid 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:
Mitochondria form dynamic networks in cells, which are maintained by fusion and fission events and whose shape adapt to altered physiological demands and stress conditions. Various regulatory circuits determine the morphology of mitochondria. At the level of the mitochondrial inner membrane, proteolytic processing of the dynamin-like GTPase OPA1 by two peptidases, the i-AAA protease YME1L and OMA1, balances membrane fusion and fission. Stress conditions associated with a dysfunction of mitochondria activate OMA1 and increase OPA1 processing, resulting in the inhibition of fusion and mitochondrial fragmentation. At the same time, OMA1 cleaves DELE1 and regulates a transcriptional stress response, termed the integrated stress response, which triggers metabolic adaptations to mitochondrial deficiencies. This mechanism thus links morphological changes in the morphology of mitochondria to stress signalling and different metabolic functions. 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 in the spinal cord. However, given the different functions of OMA1, it remained speculative whether altered OPA1 processing and mitochondrial fragmentation or impaired stress signalling and altered metabolic functions of OMA1 cause these deficiencies.
To examine the role of OPA1 processing and mitochondrial fragmentation in various tissues, we have generated mouse lines by CRISPR/Cas9-mediated genome editing of the Opa1 locus, which express defined OPA1 forms that can either only be cleaved by OMA1 or cannot be efficiently cleaved. These mouse lines allow to analyse consequences of impaired OPA1 processing in tissues expressing OMA1 and disconnect OMA1 functions for mitochondrial morphology and metabolism. Together with knockout mouse lines lacking OMA1 or DELE1, several outstanding questions will be addressed:
- How does mitochondrial fragmentation affect the survival of cardiomyocytes and neurons?
- Does stress-induced mitochondrial fragmentation limit or extend the lifespan?
- What is the physiological role of the integrated stress response regulated by OMA1 during aging and in mitochondrial disease?
- How does the integrated stress response affect cellular metabolism independent of mitochondrial morphology?
- Is the coupling of mitochondrial fragmentation and metabolic adaptation by OMA1 mediated proteolysis critical for the survival of cardiomyocytes and neurons?
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.
- Deshwal, S., Fiedler, K.U., Langer, T. (2020) Mitochondrial proteases – multifaceted regulators of mitochondrial plasticity. Annu. Rev. Biochem., 89, 501-528: DOI: 10.1146/annurev-biochem-062917-012739
- 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. DOI: 10.1038/s41586-019-1738-6
- 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. DOI: 10.15252/emmm.201809288
- Sprenger, H.-G., Langer, T. (2019) The Good and the Bad about Mitochondrial Breakups. Trends in Cell Biology, 9(11). DOI: 10.1016/j.tcb.2019.08.003
- 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. DOI: 10.1126/science.aad0116
- Korwitz, A., Merkwirth, C., Richter-Dennerlein, R., Tröder, S.E., Sprenger, H.-G., Quiros, P.M., López-Otín, C., Rugarli, E.I., and Langer, T. (2016) Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria. J. Cell Biol. 212, 157-166. DOI: 10.1083/jcb.201507022
- Anand, R., Wai, T., Baker, M.J., Kladt, N., Schauss, A.C., Rugarli, E., and Langer, T. (2014) The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J. Cell Biol. 204, 919-929. DOI: 10.1083/jcb.201308006
- Baker, M.J., Lampe, P.A., Stojanovski, D., Korwitz, A., Anand, R., Tatsuta, T. and Langer, T. (2014) Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics. EMBO J. 33, 578-593. DOI: 10.1002/embj.201386474