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Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability

Author

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  • Ayşegül Erdem

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1
    Faculty of Biology, University of Barcelona, Avda. Diagonal 643)

  • Silvia Marin

    (Faculty of Biology, University of Barcelona, Avda. Diagonal 643
    CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III
    Institute of Biomedicine of University of Barcelona)

  • Diego A. Pereira-Martins

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1
    Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo)

  • Marjan Geugien

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1)

  • Alan Cunningham

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1)

  • Maurien G. Pruis

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1)

  • Isabel Weinhäuser

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1
    Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo)

  • Albert Gerding

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1
    University Medical Center Groningen, University of Groningen)

  • Barbara M. Bakker

    (University Medical Center Groningen, University of Groningen)

  • Albertus T. J. Wierenga

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1
    University Medical Center Groningen, University of Groningen, Hanzeplein 1)

  • Eduardo M. Rego

    (Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo)

  • Gerwin Huls

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1)

  • Marta Cascante

    (Faculty of Biology, University of Barcelona, Avda. Diagonal 643
    CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III
    Institute of Biomedicine of University of Barcelona)

  • Jan Jacob Schuringa

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1)

Abstract

Metabolic programs can differ substantially across genetically distinct subtypes of acute myeloid leukemia (AML). These programs are not static entities but can change swiftly as a consequence of extracellular changes or in response to pathway-inhibiting drugs. Here, we uncover that AML patients with FLT3 internal tandem duplications (FLT3-ITD+) are characterized by a high expression of succinate-CoA ligases and high activity of mitochondrial electron transport chain (ETC) complex II, thereby driving high mitochondrial respiration activity linked to the Krebs cycle. While inhibition of ETC complex II enhances apoptosis in FLT3-ITD+ AML, cells also quickly adapt by importing lactate from the extracellular microenvironment. 13C3-labelled lactate metabolic flux analyses reveal that AML cells use lactate as a fuel for mitochondrial respiration. Inhibition of lactate transport by blocking Monocarboxylic Acid Transporter 1 (MCT1) strongly enhances sensitivity to ETC complex II inhibition in vitro as well as in vivo. Our study highlights a metabolic adaptability of cancer cells that can be exploited therapeutically.

Suggested Citation

  • Ayşegül Erdem & Silvia Marin & Diego A. Pereira-Martins & Marjan Geugien & Alan Cunningham & Maurien G. Pruis & Isabel Weinhäuser & Albert Gerding & Barbara M. Bakker & Albertus T. J. Wierenga & Eduar, 2022. "Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29639-0
    DOI: 10.1038/s41467-022-29639-0
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    References listed on IDEAS

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    1. Kiyomi Morita & Feng Wang & Katharina Jahn & Tianyuan Hu & Tomoyuki Tanaka & Yuya Sasaki & Jack Kuipers & Sanam Loghavi & Sa A. Wang & Yuanqing Yan & Ken Furudate & Jairo Matthews & Latasha Little & C, 2020. "Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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