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 the 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).

In addition, ubiquitin is necessary to keep mitochondria and cells in a plastic and healthy state. We found a novel and unsuspected form of ubiquitin, UbteX, with a broad and unprecedented impact in mitochondrial dynamics and in stress responses. Now, we focus on how UbteX regulates stress responses and impact cellular survival, in concert with the ubiquitin proteasome system (UPS) and the autophagic machinery. We investigate unexplored connections between mitochondria and cellular homeostasis.

We wish to transform the relevance of mitochondrial dynamics and UbteX for quality control and aging processes into therapeutic options for neurodegenerative and obesity-linked diseases.

2. Research questions addresses 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, which we called UbteX, 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 before 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, systems 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. Previous experience with yeast or cell culture is beneficial but not required.

6. References:

• Altin S, et al and M Escobar-Henriques. manuscript in preparation, concerning quality control functions of UbteX
• Joaquim M, et al M Odenthal and M Escobar-Henriques. manuscript in preparation, concerning quality control functions of human mitofusins
• Anton V, et al Hoppe T and M Escobar-Henriques. manuscript in revision, concerning mitochondrial stress management by ubiquitin
• Buntenbroich I, et al and M Escobar-Henriques. manuscript in revision, concerning quality control functions of yeast mitofusins
• Buntenbroich I, T Simoes and M Escobar-Henriques. Analysis of Protein Stability by Synthesis Shutoff. Bio Protoc 2021 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.
• T. Simões, R. Schuster, F. den Brave and M. Escobar-Henriques (2018) Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion. Elife; Jan 8 e30015. (IF=7,617) Selected for elife digesti