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; Mohamed Elgendy

doi:10.1038/s41467-025-66831-4

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, Mohamed Elgendy (Corresponding author)

Functional and Evolutionary Ecology

Publications: Contribution to journal › Article › Peer Reviewed

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.

Original language	English
Pages (from-to)	10841
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-66831-4
Publication status	Published - 1 Dec 2025

Austrian Fields of Science 2012

301904 Cancer research

Keywords

Myeloid Cell Leukemia Sequence 1 Protein/metabolism
Mechanistic Target of Rapamycin Complex 1/metabolism
Animals
Humans
Signal Transduction
Energy Metabolism
Mice
Carcinogenesis/metabolism
Hexokinase/metabolism
Apoptosis
Cell Line, Tumor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-025-66831-4

Cite this

Gui, W., Paral, P., Dhamija, B., Hagag, E., Dusa, M., Humajova, J., Francova, P. V., Kucka, J., Pankrac, J., Schütz, C., Armenis, V., Ferrucci, F., Schubert, M., Guan, K., Baenke, F., Stange, D. E., Lehmann, L. H., Weckwerth, W., Mirtschink, P., ... Elgendy, M. (2025). MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis. Nature Communications, 16(1), 10841. https://doi.org/10.1038/s41467-025-66831-4

@article{9906e07f788c48029361f9f85fc4beb8,

title = "MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis",

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.",

keywords = "Myeloid Cell Leukemia Sequence 1 Protein/metabolism, Mechanistic Target of Rapamycin Complex 1/metabolism, Animals, Humans, Signal Transduction, Energy Metabolism, Mice, Carcinogenesis/metabolism, Hexokinase/metabolism, Apoptosis, Cell Line, Tumor",

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Gui, W, Paral, P, Dhamija, B, Hagag, E, Dusa, M, Humajova, J, Francova, PV, Kucka, J, Pankrac, J, Schütz, C, Armenis, V, Ferrucci, F, Schubert, M, Guan, K, Baenke, F, Stange, DE, Lehmann, LH, Weckwerth, W, Mirtschink, P, Traikov, S, Giuseppe, B, Miracco, C, Bornhäuser, M, Minucci, S, Sefc, L, Macurek, L & Elgendy, M 2025, 'MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis', Nature Communications, vol. 16, no. 1, pp. 10841. https://doi.org/10.1038/s41467-025-66831-4

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T1 - MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis

AU - Gui, Wentao

AU - Paral, Petr

AU - Dhamija, Bhavuk

AU - Hagag, Eman

AU - Dusa, Martin

AU - Humajova, Jana

AU - Francova, Pavla V

AU - Kucka, Jan

AU - Pankrac, Jan

AU - Schütz, Caroline

AU - Armenis, Vasileios

AU - Ferrucci, Filippo

AU - Schubert, Mario

AU - Guan, Kaomei

AU - Baenke, Franziska

AU - Stange, Daniel E

AU - Lehmann, Lorenz H

AU - Weckwerth, Wolfram

AU - Mirtschink, Peter

AU - Traikov, Sofia

AU - Giuseppe, Belmonte

AU - Miracco, Clelia

AU - Bornhäuser, Martin

AU - Minucci, Saverio

AU - Sefc, Ludek

AU - Macurek, Libor

AU - Elgendy, Mohamed

PY - 2025/12/1

Y1 - 2025/12/1

N2 - 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.

AB - 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.

KW - Myeloid Cell Leukemia Sequence 1 Protein/metabolism

KW - Mechanistic Target of Rapamycin Complex 1/metabolism

KW - Animals

KW - Humans

KW - Signal Transduction

KW - Energy Metabolism

KW - Mice

KW - Carcinogenesis/metabolism

KW - Hexokinase/metabolism

KW - Apoptosis

KW - Cell Line, Tumor

U2 - 10.1038/s41467-025-66831-4

DO - 10.1038/s41467-025-66831-4

M3 - Article

C2 - 41326406

SN - 2041-1723

VL - 16

SP - 10841

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis

Abstract

Austrian Fields of Science 2012

Keywords

UN SDGs

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