MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis

Author(s): Wentao Gui, Petr Paral, Bhavuk Dhamija, Eman Hagag, Martin Dusa, Jana Humajova, Pavla V Francova, Jan Kucka, Jan Pankrac, Caroline Schütz, Vasileios Armenis, Filippo Ferrucci, Mario Schubert, Kaomei Guan, Franziska Baenke, Daniel E Stange, Lorenz H Lehmann, Wolfram Weckwerth, Peter Mirtschink, Sofia Traikov, Belmonte Giuseppe, Clelia Miracco, Martin Bornhäuser, Saverio Minucci, Ludek Sefc, Libor Macurek, Mohamed Elgendy
Abstract: Myeloid cell leukemia-1 (MCL1) is among the most overexpressed proteins in tumors. MCL1 contributes to tumorigenesis by antagonizing apoptosis. However, apoptosis-unrelated functions are emerging. Screening an array of signaling switches identifies mTORC1 to be modulated by MCL1 but not by the anti-apoptotic Bcl-2 or Bcl-xL. mTORC1 is a central metabolic regulator. MCL1 impacts metabolism via modulating the expression of hexokinase 2 (HK2) in an mTORC1-dependent manner, which ultimately contributes to the tumor-promoting effects of MCL1. MCL1 inhibitors suppress mTORC1 in tumor cells but are associated with cardiotoxicity due to mTORC1 inhibition in the heart. Dietary leucine supplementation rescues mTORC1 signaling in the hearts of humanized Mcl-1 mice and greatly ameliorates the cardiotoxicity of MCL1 inhibitors. Taken together, here we describe tumor-promoting roles for MCL1 in regulating mTORC1 signaling and subsequently in bioenergetics, besides its role in antagonizing apoptosis, identifying MCL1 as a hinge of cell bioenergetics and survival.
Organisation(s): Functional and Evolutionary Ecology
External organisation(s): Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic., Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic., Technische Universität Dresden, Charles University Prague, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic., Mildred-Scheel Early Career Center, National Center for Tumor Diseases Dresden (NCT/UCC) University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany., Institute of Pharmacology and Toxicology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Helmholtz-Zentrum Dresden-Rossendorf, Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus Dresden, Dresden, Germany., Stiftung Deutsches Krebsforschungszentrum, Vienna Metabolomics Center (VIME), University of Vienna, Vienna, Austria., Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany., Section of Pathological Anatomy, Department of Medicine, Surgery and Neuroscience, University Hospital of Siena, Siena, Italy., National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany., Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy; Department of Hemato-Oncology, Università Statale di Milano, Milan, Italy., Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic., Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. mohamed.elgendy@ukdd.de., Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. mohamed.elgendy@ukdd.de., Mildred-Scheel Early Career Center, National Center for Tumor Diseases Dresden (NCT/UCC) University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. mohamed.elgendy@ukdd.de., Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic. mohamed.elgendy@ukdd.de., National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany. mohamed.elgendy@ukdd.de.
Journal: Nature Communications
Volume: 16
Pages: 10841
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-025-66831-4
Publication date: 12-2025
Peer reviewed: Yes
Austrian Fields of Science 2012: 301904 Cancer research
Keywords
Portal url: https://ucrisportal.univie.ac.at/en/publications/9906e07f-788c-4802-9361-f9f85fc4beb8