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

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 wit...

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Autores: Erdem, Aysegül, Marín Martínez, Silvia, Pereira-Martins, Diego A., Geugien, Marjan, Cunningham, Alan, Pruis, Maurien G., Weinhäuser, Isabel, Gerding, Albert, Bakker, Barbara M., Wierenga, Albertus, Rego, Eduardo, Huls, Gerwin, Cascante i Serratosa, Marta, Schuringa, Jan Jacob
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/226882
Acceso en línea:https://hdl.handle.net/2445/226882
Access Level:acceso abierto
Palabra clave:Leucèmia mieloide
Aparell respiratori
Metabolisme
Myeloid leukemia
Respiratory organs
Metabolism
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repository_id_str
spelling Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerabilityErdem, AysegülMarín Martínez, SilviaPereira-Martins, Diego A.Geugien, MarjanCunningham, AlanPruis, Maurien G.Weinhäuser, IsabelGerding, AlbertBakker, Barbara M.Wierenga, AlbertusRego, EduardoHuls, GerwinCascante i Serratosa, MartaSchuringa, Jan JacobLeucèmia mieloideAparell respiratoriMetabolismeMyeloid leukemiaRespiratory organsMetabolismMetabolic 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.Nature Publishing Group2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/226882Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41467-022-29639-0Nature Communications, 2022, vol. 13, num.1https://doi.org/10.1038/s41467-022-29639-0cc-by (c) Erdem, A. et al., 2022http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2268822026-05-27T06:46:51Z
dc.title.none.fl_str_mv Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
title Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
spellingShingle Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
Erdem, Aysegül
Leucèmia mieloide
Aparell respiratori
Metabolisme
Myeloid leukemia
Respiratory organs
Metabolism
title_short Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
title_full Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
title_fullStr Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
title_full_unstemmed Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
title_sort Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
dc.creator.none.fl_str_mv Erdem, Aysegül
Marín Martínez, Silvia
Pereira-Martins, Diego A.
Geugien, Marjan
Cunningham, Alan
Pruis, Maurien G.
Weinhäuser, Isabel
Gerding, Albert
Bakker, Barbara M.
Wierenga, Albertus
Rego, Eduardo
Huls, Gerwin
Cascante i Serratosa, Marta
Schuringa, Jan Jacob
author Erdem, Aysegül
author_facet Erdem, Aysegül
Marín Martínez, Silvia
Pereira-Martins, Diego A.
Geugien, Marjan
Cunningham, Alan
Pruis, Maurien G.
Weinhäuser, Isabel
Gerding, Albert
Bakker, Barbara M.
Wierenga, Albertus
Rego, Eduardo
Huls, Gerwin
Cascante i Serratosa, Marta
Schuringa, Jan Jacob
author_role author
author2 Marín Martínez, Silvia
Pereira-Martins, Diego A.
Geugien, Marjan
Cunningham, Alan
Pruis, Maurien G.
Weinhäuser, Isabel
Gerding, Albert
Bakker, Barbara M.
Wierenga, Albertus
Rego, Eduardo
Huls, Gerwin
Cascante i Serratosa, Marta
Schuringa, Jan Jacob
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Leucèmia mieloide
Aparell respiratori
Metabolisme
Myeloid leukemia
Respiratory organs
Metabolism
topic Leucèmia mieloide
Aparell respiratori
Metabolisme
Myeloid leukemia
Respiratory organs
Metabolism
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/226882
url https://hdl.handle.net/2445/226882
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41467-022-29639-0
Nature Communications, 2022, vol. 13, num.1
https://doi.org/10.1038/s41467-022-29639-0
dc.rights.none.fl_str_mv cc-by (c) Erdem, A. et al., 2022
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Erdem, A. et al., 2022
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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