Erdem 2022 Nat Commun
Erdem A, Marin S, Pereira-Martins DA, Geugien M, Cunningham A, Pruis MG, WeinhΓ€user I, Gerding A, Bakker BM, Wierenga ATJ, Rego EM, Huls G, Cascante M, Schuringa JJ (2022) Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability. https://doi.org/10.1038/s41467-022-29639-0 |
Β» Nat Commun 13:2013. PMID: 35440568 Open Access
Erdem Ayseguel, Marin Silvia, Pereira-Martins Diego A, Geugien Marjan, Cunningham Alan, Pruis Maurien G, Weinhaeuser Isabel, Gerding Albert, Bakker Barbara M, Wierenga Albertus TJ, Rego Eduardo M, Huls Gerwin, Cascante Marta, Schuringa Jan Jacob (2022) Nat Commun
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.
β’ Bioblast editor: Plangger M β’ O2k-Network Lab: NL Groningen Reijngoud RJ, NL Groningen Reijngoud RJ
Labels: MiParea: Respiration
Pathology: Cancer
Organism: Human Tissue;cell: Other cell lines Preparation: Permeabilized cells
Coupling state: LEAK, OXPHOS, ET
Pathway: N
HRR: Oxygraph-2k
2022-11