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

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, Eduardo M Rego, Gerwin Huls, Marta Cascante, Jan Jacob Schuringa*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number2013
Number of pages15
JournalNature Communications
Issue number1
Publication statusPublished - Dec-2022


  • Apoptosis
  • Cell Line, Tumor
  • Humans
  • Lactic Acid
  • Leukemia, Myeloid, Acute/genetics
  • Mutation
  • Oxidoreductases
  • Tumor Microenvironment
  • fms-Like Tyrosine Kinase 3/genetics

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