MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis

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 and Mohamed Elgendy ()
Additional contact information
Wentao Gui: Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
Petr Paral: Charles University, Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine
Bhavuk Dhamija: Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
Eman Hagag: Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
Martin Dusa: Charles University, Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine
Jana Humajova: Charles University, Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine
Pavla V. Francova: Charles University, Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine
Jan Kucka: Czech Academy of Sciences, Institute of Macromolecular Chemistry
Jan Pankrac: Charles University, Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine
Caroline Schütz: Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
Vasileios Armenis: Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
Filippo Ferrucci: Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
Mario Schubert: Technische Universität Dresden, Institute of Pharmacology and Toxicology, Medizinische Fakultät Carl Gustav Carus
Kaomei Guan: Technische Universität Dresden, Institute of Pharmacology and Toxicology, Medizinische Fakultät Carl Gustav Carus
Franziska Baenke: University Hospital Carl Gustav Carus Dresden, Department of Visceral, Thoracic and Vascular Surgery
Daniel E. Stange: University Hospital Carl Gustav Carus Dresden, Department of Visceral, Thoracic and Vascular Surgery
Lorenz H. Lehmann: University Hospital Heidelberg, Department of Cardiology
Wolfram Weckwerth: University of Vienna, Department of Functional and Evolutionary Ecology, Molecular Systems Biology (MOSYS)
Peter Mirtschink: Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
Sofia Traikov: Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
Belmonte Giuseppe: University Hospital of Siena, Section of Pathological Anatomy, Department of Medicine, Surgery and Neuroscience
Clelia Miracco: University Hospital of Siena, Section of Pathological Anatomy, Department of Medicine, Surgery and Neuroscience
Martin Bornhäuser: Technische Universität Dresden, Medical Clinic I, University Hospital Carl Gustav Carus
Saverio Minucci: Università Statale di Milano, Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy; Department of Hemato-Oncology
Ludek Sefc: Charles University, Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine
Libor Macurek: Institute of Molecular Genetics of the Czech Academy of Sciences, Cancer Cell Biology
Mohamed Elgendy: Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-66831-4

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