1. Research Background:

Cellular performance is strongly dependent on morphological changes of mitochondria, controlled by tailored and coordinated adaptations of mitochondrial dynamics. This plasticity requires mitofusin proteins, age-related disease gatekeepers that mediate fusion events. Mitofusin defects cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A) and affect the pathogenesis of many common age-related diseases, such as non-alcoholic fatty liver disease (NAFLD).

Ubiquitin and other post-translational modifiers are necessary to keep mitochondria and cells in a plastic and healthy state. We found a novel and unsuspected form of ubiquitin, CxUb, with a broad and unprecedented impact in mitochondrial dynamics and in stress responses. We investigate how CxUb regulates stress responses and impacts survival and longevity, in concert with the ubiquitin proteasome system (UPS) and the autophagic machinery. We explore these connections between mitochondria and cellular homeostasis using yeast, worms and human cell lines.

We wish to transform the relevance of mitochondrial dynamics and CxUb into therapeutic options for neurodegenerative and obesity-linked diseases.

2. Research questions addressed by the group:

Our research intertwines mitochondria and ubiquitin: We are interested in several aspects of mitochondrial dynamics and quality-control processes, critical for aging processes, which are regulated by ubiquitin:

• Unveiling the molecular mechanisms allowing ubiquitin to either promote mitochondrial fusion or drive mitochondrial fragmentation, in response to proteotoxic stress or metabolic changes.
• Elucidating the pathways accounting for the disease gatekeeper role of mitofusins, by investigating how mitofusin ubiquitylation ensures a proper communication between mitochondria and its cellular environment.
• Understanding how novel forms of ubiquitin control protein homeostasis, stress resistance and cellular viability, by identifying the molecular targets and ubiquitin ligases involved.
• Exploring networks between deubiquitylases, the endocytic machinery and proteasomal degradation, to resist ribosomal defects, conferring stress resilience.
• Identifying biomarkers and exploring therapeutic strategies for neurodegenerative and liver diseases.

3. Possible projects:

Several projects addressing the questions outlined above are possible and should be directly discussed, to find the best interest match between the PhD candidate and our group.

4. Applied Methods and model organisms:

• Methods: cellular biology, molecular biology, genetics and biochemistry
• Model organisms: yeast and human/mouse cell lines. Mouse models and worms, via ongoing collaborations.

5. Desirable skills and qualifications:

Most important are scientific curiosity, motivation, flexibility, resilience and team work skills. Background in mitochondria or protein homeostasis is a plus. Previous experience with yeast or cell culture is beneficial but not required.

6. References:

• S. Altin, T. Simões, […], A. Reichert and M. Escobar-Henriques, “Universally conserved ubiquitin precursor is essential for cellular homeostasis under stress and aging” – submitted.
• M. Joaquim, […], M. Odenthal and M. Escobar-Henriques, “Mitofusin 2 displays fusion-independent roles in proteostasis surveillance” – revised version under evaluation.
• V. Anton, I. Buntenbroich, T. Simões, M. Joaquim, L. Müller, R. Büttner, M. Odenthal, T. Hoppe and M. Escobar-Henriques (2023). “E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response”, Molecular Cell, Aug 17;83(16):2976-2990.e9. doi: 10.1016/j.molcel.2023.07.021
• I. Buntenbroich, V. Anton, D. Perez-Hernandez, T. Simões, F. Babatz Gaedke, A. Schauss, G. Dittmar, J. Riemer and M. Escobar-Henriques (2023) “Novel docking and stability steps in mitochondrial fusion highlight the proteasome as potential therapeutic target”, iScience, Jun 7;26(7):107014. doi: 10.1016/j.isci.2023.107014
• Buntenbroich I, T Simoes and M Escobar-Henriques. Analysis of Protein Stability by Synthesis Shutoff. Bio Protoc2021 11(22): e4225.
• M. Joaquim and M. Escobar-Henriques (2020) “Role of mitofusins and mitophagy in life or death decisions”, Front. Cell Dev. Biol., eCollection, 2020, 8:572182. doi: 10.3389/fcell.2020.572182.
• M. Escobar-Henriques and V. Anton (2020) “Mitochondrial Surveillance by Cdc48/p97: MAD vs Membrane Fusion”, Int J Mol Sci. 2020, 21(18):6841. doi: 10.3390/ijms21186841.
• Schuster, V. Anton, T. Simões, S. Altin, F. den Brave, T. Hermanns, M. Hospenthal, D. Komander, G. Dittmar, J.R. Dohmen and M. Escobar-Henriques (2020) “Dual role of a GTPase conformational switch for membrane fusion by mitofusin ubiquitylation” , Life Sci Alliance. 19;3(1). e201900476. doi: 10.26508/lsa.201900476.
• V. Anton, I. Buntenbroich, R. Schuster, F. Babatz, T. Simões, S. Altin, G. Calabrese, J. Riemer, A.C. Schauss and M. Escobar-Henriques (2019) "Plasticity in salt-bridge allows fusion-competent ubiquitylation of mitofusins and Cdc48 recognition", Life Sci Alliance. 18;2(6). e201900491. doi: 10.26508/lsa.201900491
• M. Escobar-Henriques and M. Joaquim (2019) “Mitofusins: Disease gatekeepers and hubs in mitochondrial quality control by E3 ligases”, Front. Physiol, eCollection 2019, 10:517. doi: 10.3389/fphys.2019.00517.R.
• M. Escobar-Henriques, S. Altin and F. den Brave (2019) Interplay between the ubiquitin proteasome system and mitochondria for protein homeostasis. Current Issues in Molecular Biology. 18;35:35-58
• M. Escobar-Henriques and M. Joaquim (2019). Mitofusins: Disease Gatekeepers and Hubs in Mitochondrial Quality Control by E3 Ligases. Front Physiol 10, 517.