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 (Korresp. Autor*in)

Department für Funktionelle und Evolutionäre Ökologie

Veröffentlichungen: Beitrag in Fachzeitschrift › Artikel › 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.

Originalsprache	Englisch
Aufsatznummer	10841
Fachzeitschrift	Nature Communications
Jahrgang	16
Ausgabenummer	1
DOIs	https://doi.org/10.1038/s41467-025-66831-4
Publikationsstatus	Veröffentlicht - 1 Dez. 2025

Fördermittel

We are thankful to Dr. Manja Wobus for providing AML cells and to Dr. David Huang and Dr. Anna García-Saéz for providing WT and Bax/Bak DKO MEFs and to Dr Marco Herold for providing the huMcl-1 mice. We are also thankful for Dr. Tomáš Mráček and Dr. Alena Pecinová for their kind help with metabolic analysis of heart tissues. M.E. has received funding from the European Research Council (ERC) under Horizon 2020 research and innovation programme (Onco-Energetics_OFF, grant agreement no. 852761) and the German Research Foundation (Project No. EL 1081/2-1) and has received partial support from Czech Science Foundation (GACR) (project no. 19-22156Y). L.S. has received funding from The Czech Science Foundation (GACR) Lead Agency (Weave) (Project No. 22-16819 K) and Czech-BioImaging large RI project (LM2023050 funded by MEYS CR) and GACR European Regional Development Fund (Project No. CZ.02.1.01/0.0/0.0/16_013/0001775) supported imaging lab and instrument funding. P. V.-F. has been partially supported as a student by Charles University grant SVV 260519/2023. L.M. and W.G. were partially supported by the National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102).

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

ÖFOS 2012

301904 Krebsforschung

Zugriff auf Dokument

10.1038/s41467-025-66831-4Lizenz: CC BY 4.0

Andere Dateien und Links

Verknüpfung zur Publikation in Scopus

Zitationsweisen

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), Artikel 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",

author = "Wentao Gui and Petr Paral and Bhavuk Dhamija and Eman Hagag and Martin Dusa and Jana Humajova and Francova, \{Pavla V\} and Jan Kucka and Jan Pankrac and Caroline Sch{\"u}tz and Vasileios Armenis and Filippo Ferrucci and Mario Schubert and Kaomei Guan and Franziska Baenke and Stange, \{Daniel E\} and Lehmann, \{Lorenz H\} and Wolfram Weckwerth and Peter Mirtschink and Sofia Traikov and Belmonte Giuseppe and Clelia Miracco and Martin Bornh{\"a}user and Saverio Minucci and Ludek Sefc and Libor Macurek and Mohamed Elgendy",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

day = "1",

doi = "10.1038/s41467-025-66831-4",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "NATURE PUBLISHING GROUP",

number = "1",

}

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, Jg. 16, Nr. 1, 10841. https://doi.org/10.1038/s41467-025-66831-4

TY - JOUR

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

UR - https://www.scopus.com/pages/publications/105023570596

U2 - 10.1038/s41467-025-66831-4

DO - 10.1038/s41467-025-66831-4

M3 - Article

C2 - 41326406

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 10841

ER -

MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis

Abstract

Fördermittel

UN SDGs

ÖFOS 2012

Zugriff auf Dokument

Andere Dateien und Links

Fingerprint

Zitationsweisen