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MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis

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  • Wentao Gui

    (Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
    Technische Universität Dresden, Medical Clinic I, University Hospital Carl Gustav Carus
    Technische Universität Dresden, Mildred-Scheel Early Career Center, National Center for Tumor Diseases Dresden (NCT/UCC) University Hospital and Faculty of Medicine
    Institute of Molecular Genetics of the Czech Academy of Sciences, Cancer Cell Biology)

  • Petr Paral

    (Charles University, Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine
    Charles University, Institute of Pathological Physiology, First Faculty of Medicine)

  • Bhavuk Dhamija

    (Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
    Technische Universität Dresden, Medical Clinic I, University Hospital Carl Gustav Carus)

  • Eman Hagag

    (Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
    Technische Universität Dresden, Medical Clinic I, University Hospital Carl Gustav Carus)

  • 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
    Technische Universität Dresden, Medical Clinic I, University Hospital Carl Gustav Carus)

  • Vasileios Armenis

    (Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
    Technische Universität Dresden, Medical Clinic I, University Hospital Carl Gustav Carus)

  • Filippo Ferrucci

    (Technische Universität Dresden, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine
    Technische Universität Dresden, Medical Clinic I, University Hospital Carl Gustav Carus
    Technische Universität Dresden, Mildred-Scheel Early Career Center, National Center for Tumor Diseases Dresden (NCT/UCC) 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
    German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden
    Helmholtz-Zentrum Dresden—Rossendorf (HZDR))

  • 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
    Heidelberg, German Center for Cardiovascular Research (DZHK)
    German Cancer Research Center (DKFZ))

  • Wolfram Weckwerth

    (University of Vienna, Department of Functional and Evolutionary Ecology, Molecular Systems Biology (MOSYS)
    University of Vienna, Vienna Metabolomics Center (VIME))

  • 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
    German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden)

  • 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
    Technische Universität Dresden, Medical Clinic I, University Hospital Carl Gustav Carus
    Technische Universität Dresden, Mildred-Scheel Early Career Center, National Center for Tumor Diseases Dresden (NCT/UCC) University Hospital and Faculty of Medicine
    Institute of Molecular Genetics of the Czech Academy of Sciences, Cancer Cell Biology)

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.

Suggested Citation

  • 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 Schub, 2025. "MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-66831-4
    DOI: 10.1038/s41467-025-66831-4
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