MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis
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.
Authors
- Daniel E. Stange (ORCID: https://orcid.org/0000-0003-4246-2230)
- Petr Páral (ORCID: https://orcid.org/0000-0003-2308-9688)
- Lorenz Lehmann (ORCID: https://orcid.org/0000-0001-5077-8580)
- Sofia Traikov
- Eman Hagag (ORCID: https://orcid.org/0009-0003-7650-3798)
- Jana Humajová
- Martin Bornhäuser (ORCID: https://orcid.org/0000-0002-5916-3029)
- Vasileios Armenis (ORCID: https://orcid.org/0000-0002-8340-5462)
- Wentao Gui (ORCID: https://orcid.org/0000-0002-4276-8312)
- Saverio Minucci (ORCID: https://orcid.org/0000-0001-5678-536X)
- Mario Schubert (ORCID: https://orcid.org/0000-0002-8375-8233)
- Franziska Baenke (ORCID: https://orcid.org/0000-0001-9389-4688)
- Catharina Schütz (ORCID: https://orcid.org/0009-0003-6519-0482)
- Luděk Šefc (ORCID: https://orcid.org/0000-0003-2846-220X)
- Filippo Ferrucci
- Jan Kučka (ORCID: https://orcid.org/0000-0003-2489-5315)
- Libor Macůrek (ORCID: https://orcid.org/0000-0002-0987-1238)
- Pavla Francová (ORCID: https://orcid.org/0000-0003-0210-5378)
- Jan Pankrác (ORCID: https://orcid.org/0000-0002-9574-1391)
- Wolfram Weckwerth (ORCID: https://orcid.org/0000-0002-9719-6358)
- Bhavuk Dhamija (ORCID: https://orcid.org/0000-0002-2015-2234)
- Peter Mirtschink (ORCID: https://orcid.org/0000-0001-5832-1673)
- Clelia Miracco (ORCID: https://orcid.org/0000-0001-7642-7404)
- Kaomei Guan (ORCID: https://orcid.org/0000-0002-0753-3083)
- Mohamed Elgendy (ORCID: https://orcid.org/0000-0002-5598-1067)
- Martin Dusa
- Belmonte Giuseppe
Institutions
- University of Siena (IT)
- University of Vienna (AT)
- German Cancer Research Center (DE)
- University of Milan (IT)
- Charles University (CZ)
- Heidelberg University (DE)
- Helmholtz-Zentrum Dresden-Rossendorf (DE)
- University Hospital Heidelberg (DE)
- Czech Academy of Sciences, Institute of Macromolecular Chemistry (CZ)
- National Center for Tumor Diseases (DE)
- German Centre for Cardiovascular Research (DE)
- Institute of Molecular Genetics (RU)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- University Hospital Carl Gustav Carus (DE)
- European Institute of Oncology (IT)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1038/s41467-025-66831-4
- Citations
- 2
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61