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.

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:

M. Escobar-Henriques and K. F. Winklhofer (2026). “Integration of mitochondria into the cellular proteostasis network”. invited contribution, addressing minor revisions, Review, available upon request

M. Joaquim, M.F. Dohrn, A. Chevrollier and M. Escobar-Henriques (2026). “Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease”. Autophagy reports. 5(1):2629624. doi: 10.1080/27694127.2026.2629624. eCollection 2026.

M. Joaquim, M.B. Bulimaga, […], M. Escobar-Henriques (2025) “Charcot Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death” – J Cell Science, 138(18). doi: 10.1242/jcs.263691.

S. Altin, T. Simões, C. Behrendt, V. Anton, […], M. Escobar-Henriques (2025) “Ubiquitin Precursor with C-terminal Extension promotes Proteostasis and Longevity” – Molecular Cell, 85(19):3677-3693. doi: 10.1016/j.molcel.2025.08.032.

M. Joaquim, S. Altin, M.-B. Bulimaga, […], M. Escobar-Henriques (2025) “Mitofusin 2 displays fusion-independent roles in proteostasis surveillance” – Nature commun., 16, 1501. doi: 10.1038/s41467-025-56673-5.

V. Anton, I. Buntenbroich, […], M. Escobar-Henriques (2023) “E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response”, Molecular Cell, Aug 17;83(16):2976-2990. doi: 10.1016/j.molcel.2023.07.021.