Center for Molecular Medicine Cologne

Escobar-Henriques, Mafalda | Margarete Odenthal - A 02

The role of MFN2 in CMT2A neurodegeneration and in NAFLD liver disease

Introduction

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).

Our Aims

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

Own Previous Work

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).
  • Perne, C., S. Peters, M. Cartolano, S. Horpaopan, C. Grimm, J. Altmuller, A.K. Sommer, A.M. Hillmer, H. Thiele, M. Odenthal, G. Moslein, R. Adam, S. Sivalingam, J. Kirfel, M.R. Schweiger, M. Peifer, I. Spier, and S. Aretz, Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis. PLoS One, 2021. 16(11): p. e0259185.
  • Li, J., X. Wu, L. Schiffmann, T. MacVicar, C. Zhou, Z. Wang, D. Li, O.V. Camacho, R. Heuchel, M. Odenthal, A. Hillmer, A. Quaas, Y. Zhao, C.J. Bruns, and F.C. Popp, IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth. Cancers (Basel), 2021. 13(21).
  • Czauderna, C., A. Poplawski, C.J. O'Rourke, D. Castven, B. Perez-Aguilar, D. Becker, S. Heilmann-Heimbach, M. Odenthal, W. Amer, M. Schmiel, U. Drebber, H. Binder, D.A. Ridder, M. Schindeldecker, B.K. Straub, P.R. Galle, J.B. Andersen, S.S. Thorgeirsson, Y.N. Park, and J.U. Marquardt, Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis. JCI Insight, 2021. 6(17).
  • Ullah, A., I.U. Rehman, J. Ahmad, M. Odenthal, S. Ahmad, T. Nadeem, Q. Ali, M. Rizwan, M.A. Khan, S. Hassan, H. Ahsan, and B. Ahmad, Phylogenetic analysis of the 5' untranslated region of HCV from cirrhotic patients in Khyber Pakhtunkhwa, Pakistan. Sci Rep, 2021. 11(1): p. 15023.
  • Wu, F., J. Fan, Y. He, A. Xiong, J. Yu, Y. Li, Y. Zhang, W. Zhao, F. Zhou, W. Li, J. Zhang, X. Zhang, M. Qiao, G. Gao, S. Chen, X. Chen, X. Li, L. Hou, C. Wu, C. Su, S. Ren, M. Odenthal, R. Buettner, N. Fang, and C. Zhou, Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nat Commun, 2021. 12(1): p. 2540.
  • Churin, Y., K. Irungbam, C.S. Imiela, D. Schwarz, H.J. Mollenkopf, U. Drebber, M. Odenthal, O. Pak, M. Huber, D. Glebe, M. Roderfeld, and E. Roeb, Lipid Storage and Interferon Response Determine the Phenotype of Ground Glass Hepatocytes in Mice and Humans. Cell Mol Gastroenterol Hepatol, 2021. 12(2): p. 383-394.
  • Kanne J, Hussong M, Isensee J, Munoz-Lopez A, Wolffgramm J, Hess F, Grimm C, Bessonov S, Meder L, Wang J, Reinhardt HC, Odenthal M, Hucho T, Buttner R, Summerer D, and Schweiger MR (2021). Pericentromeric Satellite III transcripts induce etoposide resistance. Cell Death Dis12, 530. doi:10.1038/s41419-021-03810-9.   
  • Meder L, Florin A, Ozretic L, Nill M, Koker M, Meemboor S, Radtke F, Diehl L, Ullrich RT, Odenthal M, Buttner R, and Heukamp LC (2021). Notch1 Deficiency Induces Tumor Cell Accumulation Inside the Bronchiolar Lumen and Increases TAZ Expression in an Autochthonous Kras (LSL-G12V) Driven Lung Cancer Mouse Model. Pathol Oncol Res27, 596522. doi:10.3389/pore.2021.596522.
  • Klionsky, D.J., A.K. Abdel-Aziz, S. Abdelfatah, M. Abdellatif, A. Abdoli, S. Abel, H. Abeliovich, M.H. et al. , A. Esclatine, M. Escobar-Henriques, E.L. Eskelinen, L. Espert, M.O. Eusebio, G. Fabrias, C. Fabrizi, A. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)(1). Autophagy, 2021. 17(1): p. 1-382.
  • Weglage, J., F. Wolters, L. Hehr, J. Lichtenberger, C. Wulz, F. Hempel, A. Baier, T. Quack, K. Kohler, T. Longerich, G. Schramm, K. Irungbam, H. Mueller, V. von Buelow, A. Tschuschner, M. Odenthal, U. Drebber, M.E. Arousy, L.N.Z. Ramalho, K. Bankov, P. Wild, J. Pons-Kuhnemann, J. Tschammer, C.G. Grevelding, E. Roeb, and M. Roderfeld, Schistosoma mansoni eggs induce Wnt/beta-catenin signaling and activate the protooncogene c-Jun in human and hamster colon. Sci Rep, 2020. 10(1): p. 22373.
  • Meinrath, J., A. Haak, N. Igci, P. Dalvi, C. Arolt, S. Meemboor, U. Siebolts, H. Eischeidt-Scholz, C. Wickenhauser, I. Grunewald, U. Drebber, R. Buttner, A. Quaas, J.P. Klussmann, M. Odenthal, D. Beutner, and M. Meyer, Expression profiling on subclasses of primary parotid gland carcinomas. Oncotarget, 2020. 11(45): p. 4123-4137.
  • Rheinwalt, K.P., U. Drebber, R. Schierwagen, S. Klein, U.P. Neumann, T.F. Ulmer, A. Plamper, A. Kroh, S. Schipper, M. Odenthal, F.E. Uschner, P. Lingohr, J. Trebicka, and M.J. Brol, Baseline Presence of NAFLD Predicts Weight Loss after Gastric Bypass Surgery for Morbid Obesity. J Clin Med, 2020. 9(11).
  • Wu, X., J. Li, A. Gassa, D. Buchner, H. Alakus, Q. Dong, N. Ren, M. Liu, M. Odenthal, D. Stippel, C. Bruns, Y. Zhao, and R. Wahba, Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int J Biol Sci, 2020. 16(9): p. 1551-1562.
  • Wu F, Fan J, Fang J, Dalvi PS, Odenthal M, Fang N.: Single Cell Sequencing: A New Dimension in Cancer Diagnosis and Treatment. Adv Exp Med Biol. 2020;1255:109-121. doi: 10.1007/978-981-15-4494-1_9. PMID: 32949394 Review.
  • Kuiper-Makris C, Zanetti D, Vohlen C, Fahle L, Muller M, Odenthal M, Felderhoff-Muser U, Dotsch J, and Alejandre Alcazar MA (2020). Mendelian randomization and experimental IUGR reveal the adverse effect of low birth weight on lung structure and function. Sci Rep 10, 22395.
  • Escobar-Henriques M, Altin S, and Brave FD (2020). Interplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis. Curr Issues Mol Biol 35, 35-58.
  • Escobar-Henriques M, and Anton V (2020). Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion. Int J Mol Sci 21.
  • Joaquim M, and Escobar-Henriques M (2020). Role of Mitofusins and Mitophagy in Life or Death Decisions. Front Cell Dev Biol 8, 572182.
  • Schuster R, Anton V, Simoes T, Altin S, den Brave F, Hermanns T, Hospenthal M, Komander D, Dittmar G, Dohmen RJ, and Escobar-Henriques M (2020). Dual role of a GTPase conformational switch for membrane fusion by mitofusin ubiquitylation. Life Sci Alliance 3.
Dr. Mafalda Escobar-Henriques CMMC Cologne
Dr. Mafalda Escobar-Henriques

CECAD / Institute for Genetics

CMMC - PI - A 02

CMMC - PI - CAP 14

+49 221 478 84257

+49 221 478 97295

CECAD / Institute for Genetics

Joseph-Stelzmann-Str. 26

50931 Cologne

http://www.uni-koeln.de/math-nat-fak/genetik/groups/Escobar/index.html

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Mafalda Escobar-Henriques

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Prof. Dr. Margarete Odenthal CMMC Cologne
Prof. Dr. Margarete Odenthal

Institute for General Pathology and Pathological Anatomy

CMMC - Co-PI -  A 01

CMMC - Co-PI - A 02

+49 221 478 6367

+49 221 478 6360

Institute for General Pathology and Pathological Anatomy

Kerpener Str. 62

50937 Cologne

https://pathologie.uk-koeln.de/forschung/translationale-molekularpathologie-ag-odenthal/

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Margarete Odenthal

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Group Members

Dr. Tânia Simões,PostDoc
Ira Buntenbroich, PhD Student
Vincent Anton,PhD Student
Mariana Joaquim,Internship, Otto Bayer Fellow
Andria Drousioti,Bachelor Student