Mafalda Escobar-Henriques | Margarete Odenthal - A 02

Mitochondrial dysfunction participates in many chronic diseases.  MFN2 controls mitochondrial homeostasis and loss of MFN2 function causes mitochondrial failure, leading to metabolic dysregulation and cellular stress.  We address the underlying mechanisms of MFN2 inactivation, occurring in many  diseases, including neuropathies such as the Charcot-Marie-Tooth Type 2A (CMT2A) and non-alcoholic fatty liver disease (NAFLD), one of the worldwide most common chronic  liver diseases.  

Mitofusins are key players in the control of mitochondrial dynamics, having an active role on the regulation of fusion between two of these organelles. These plastic properties are central in quality control processes and in bioenergetics and metabolism. Mitofusin 2 (MFN2) was implicated in several cellular processes such as mitophagy, apoptosis, lipid transfer and calcium homeostasis. Importantly, MFN2 point mutations cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A). MFN2 is also linked to other neurodegenerative diseases, like Parkinson’s. Finally, a role in common aging diseases was also proposed, like in cardiac defects, diabetes, and in the non-alcoholic fatty liver disease (NAFLD) and cancer, associated with metabolic dysregulation, endoplasmatic stress and mitochondrial dysfunction (Figure 1).

The main research question of this proposal is to identify disease-relevant properties of MFN2. MFN2 appears to be particularly important for the balance between fusion and mitophagy. However, the underlining mechanism is unclear. We postulate this will depend on the regulation of MFN2 and mitophagy by UbteX. Thus, UbteX could play a key role in integrated stress responses. In order to address this question, we will transfer our studies to CMT2A and NAFLD: 

1. Lay the foundations in understanding how MFN2 and UbteX allow cellular fitness
2. Determine the relevance of UbteX in CMT2A neurodegeneration
3. Investigate the therapeutic potential of MFN2 and UbteX in NAFLD

The disease-underlying function of MFN2 is ill defined. We identified novel stress-response functions of mitofusins, coordinated by a previously unsuspected ubiquitin form, UbteX. In the present studies, we will employ patient biopsies, mouse models and also human cell lines, to investigate the direct role of MFN2 and UbteX in neurodegeneration and liver dysfunction. They are based on our own work on ubiquitylation of mitofusins (1,2,5-8,11) and the characterization of molecular and metabolic changes in chronic liver  disease (3,4,9,10), dependent on MFN2.

1. Anton, V., Buntenbroich, I., Schuster, R., Babatz, F., Simões, T., Altin, S., Calabrese, G., Riemer, J., Schauss A.C., and Escobar-Henriques M. Plasticity in salt-bridge allows fusion-competent ubiquitylation of mi-tofusins and Cdc48 recognition, Life Sci Alliance, 2019. 2(6).
2. Anton, F., G. Dittmar, T. Langer, and M. Escobar-Henriques, Two deubiquitylases act on mitofusin and regulate mitochondrial fusion along independent pathways. Mol Cell, 2013. 49(3): p. 487-98.
3. Brault, C., P. Levy, S. Duponchel, M. Michelet, A. Salle, E.I. Pecheur, M.L. Plissonnier, R. Parent, E. Vericel, A.V. Ivanov, M. Demir, H.M. Steffen, M. Odenthal, F. Zoulim, and B. Bartosch, Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity. Gut, 2016. 65(1): p. 144-54.
4. Brol, M.J., F. Rosch, R. Schierwagen, F. Magdaleno, F.E. Uschner, S. Manekeller, A. Queck, K. Schwarzkopf, M. Odenthal, U. Drebber, M. Thiele, P. Lingohr, A. Plamper, G. Kristiansen, S. Lotersztajn, A. Krag, S. Klein, K.P. Rheinwalt, and J. Trebicka, Combination of CCl4 with alcoholic and metabolic injuries mimics human liver fibrosis. Am J Physiol Gastrointest Liver Physiol, 2019. 317(2): p. G182-G194.
5. Escobar-Henriques, M., Mitofusins: ubiquitylation promotes fusion. Cell Res, 2014. 24(4): p. 387-8.
6. Escobar-Henriques, M., S. Altin, and F.D. Brave, Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis. Curr Issues Mol Biol, 2019. 35: p. 35-58.
7. Escobar-Henriques, M. and M. Joaquim, Mitofusins: Disease Gatekeepers and Hubs in Mitochondrial Quality Control by E3 Ligases. Front Physiol, 2019. 10: p. 517.
8. Escobar-Henriques, M. and T. Langer, Dynamic survey of mitochondria by ubiquitin. EMBO Rep, 2014. 15(3): p. 231-43.
9. Levy, P.L., S. Duponchel, H. Eischeid, J. Molle, M. Michelet, G. Diserens, M. Vermathen, P. Vermathen, J.F. Dufour, H.P. Dienes, H.M. Steffen, M. Odenthal, F. Zoulim, and B. Bartosch, Hepatitis C virus infection triggers a tumor-like glutamine metabolism. Hepatology, 2017. 65(3): p. 789-803.
10. Rey, J.W., A. Noetel, A. Hardt, A. Canbay, H. Alakus, A. Zur Hausen, H.P. Dienes, U. Drebber, and M. Odenthal, Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 in patients with fatty liver diseases. World J Gastroenterol, 2010. 16(46): p. 5830-7.
11. Schuster, R., V. Anton, T. Simoes, S. Altin, F. den Brave, T. Hermanns, M. Hospenthal, D. Komander, G. Dittmar, R.J. Dohmen, and M. Escobar-Henriques, Dual role of a GTPase conformational switch for mem-brane fusion by mitofusin ubiquitylation. Life Sci Alliance, 2020. 3(1).