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)
- Charles University Prague, Czech Academy of Sciences, Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Stiftung Deutsches Krebsforschungszentrum, Università Degli Studi di Siena, European Institute of Oncology, Università degli Studi di Milano
- Journal
- Nature Communications
- Volume
- 16
- 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
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/9906e07f-788c-4802-9361-f9f85fc4beb8