IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29639-0.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29639-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-29639-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    2. Inmaculada Martínez-Reyes & Navdeep S. Chandel, 2020. "Mitochondrial TCA cycle metabolites control physiology and disease," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Charlotte Lussey-Lepoutre & Kate E. R. Hollinshead & Christian Ludwig & Mélanie Menara & Aurélie Morin & Luis-Jaime Castro-Vega & Seth J. Parker & Maxime Janin & Cosimo Martinelli & Chris Ottolenghi &, 2015. "Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism," Nature Communications, Nature, vol. 6(1), pages 1-9, December.
    4. 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. "Publisher Correction: Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    5. Linde A. Miles & Robert L. Bowman & Tiffany R. Merlinsky & Isabelle S. Csete & Aik T. Ooi & Robert Durruthy-Durruthy & Michael Bowman & Christopher Famulare & Minal A. Patel & Pedro Mendez & Chrysanth, 2020. "Single-cell mutation analysis of clonal evolution in myeloid malignancies," Nature, Nature, vol. 587(7834), pages 477-482, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Haochen Zhang & Elias-Ramzey Karnoub & Shigeaki Umeda & Ronan Chaligné & Ignas Masilionis & Caitlin A. McIntyre & Palash Sashittal & Akimasa Hayashi & Amanda Zucker & Katelyn Mullen & Jungeui Hong & A, 2023. "Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Aleksandr Ianevski & Kristen Nader & Kyriaki Driva & Wojciech Senkowski & Daria Bulanova & Lidia Moyano-Galceran & Tanja Ruokoranta & Heikki Kuusanmäki & Nemo Ikonen & Philipp Sergeev & Markus Vähä-Ko, 2024. "Single-cell transcriptomes identify patient-tailored therapies for selective co-inhibition of cancer clones," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Peng Dai & Lucia Ruojia Wu & Sherry Xi Chen & Michael Xiangjiang Wang & Lauren Yuxuan Cheng & Jinny Xuemeng Zhang & Pengying Hao & Weijie Yao & Jabra Zarka & Ghayas C. Issa & Lawrence Kwong & David Yu, 2021. "Calibration-free NGS quantitation of mutations below 0.01% VAF," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    4. Etienne Sollier & Jack Kuipers & Koichi Takahashi & Niko Beerenwinkel & Katharina Jahn, 2023. "COMPASS: joint copy number and mutation phylogeny reconstruction from amplicon single-cell sequencing data," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Cheryl A. C. Peretz & Vanessa E. Kennedy & Anushka Walia & Cyrille L. Delley & Andrew Koh & Elaine Tran & Iain C. Clark & Corey E. Hayford & Chris D’Amato & Yi Xue & Kristina M. Fontanez & Aaron A. Ma, 2024. "Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Brooks A. Benard & Logan B. Leak & Armon Azizi & Daniel Thomas & Andrew J. Gentles & Ravindra Majeti, 2021. "Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    7. Humberto Contreras-Trujillo & Jiya Eerdeng & Samir Akre & Du Jiang & Jorge Contreras & Basia Gala & Mary C. Vergel-Rodriguez & Yeachan Lee & Aparna Jorapur & Areen Andreasian & Lisa Harton & Charles S, 2021. "Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    8. Tuğçe Beyazay & Kendra S. Belthle & Christophe Farès & Martina Preiner & Joseph Moran & William F. Martin & Harun Tüysüz, 2023. "Ambient temperature CO2 fixation to pyruvate and subsequently to citramalate over iron and nickel nanoparticles," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    9. Xiang Ge Luo & Jack Kuipers & Niko Beerenwinkel, 2023. "Joint inference of exclusivity patterns and recurrent trajectories from tumor mutation trees," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    10. Rania El-Botty & Ludivine Morriset & Elodie Montaudon & Zakia Tariq & Anne Schnitzler & Marina Bacci & Nicla Lorito & Laura Sourd & Léa Huguet & Ahmed Dahmani & Pierre Painsec & Heloise Derrien & Soph, 2023. "Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Hao Wu & Xiufeng Zhao & Sophia M. Hochrein & Miriam Eckstein & Gabriela F. Gubert & Konrad Knöpper & Ana Maria Mansilla & Arman Öner & Remi Doucet-Ladevèze & Werner Schmitz & Bart Ghesquière & Sebasti, 2023. "Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    12. Diletta Fontana & Ilaria Crespiatico & Valentina Crippa & Federica Malighetti & Matteo Villa & Fabrizio Angaroni & Luca De Sano & Andrea Aroldi & Marco Antoniotti & Giulio Caravagna & Rocco Piazza & A, 2023. "Evolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    13. Marine Lanfranchi & Sozerko Yandiev & Géraldine Meyer-Dilhet & Salma Ellouze & Martijn Kerkhofs & Raphael Dos Reis & Audrey Garcia & Camille Blondet & Alizée Amar & Anita Kneppers & Hélène Polvèche & , 2024. "The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    14. Cesare Granata & Nikeisha J. Caruana & Javier Botella & Nicholas A. Jamnick & Kevin Huynh & Jujiao Kuang & Hans A. Janssen & Boris Reljic & Natalie A. Mellett & Adrienne Laskowski & Tegan L. Stait & A, 2021. "High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    15. Tao Zhang & Sarah E. Noll & Jesus T. Peng & Amman Klair & Abigail Tripka & Nathan Stutzman & Casey Cheng & Richard N. Zare & Alexandra J. Dickinson, 2023. "Chemical imaging reveals diverse functions of tricarboxylic acid metabolites in root growth and development," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    16. Chujiao Lin & Qiyuan Yang & Dongsheng Guo & Jun Xie & Yeon-Suk Yang & Sachin Chaugule & Ngoc DeSouza & Won-Taek Oh & Rui Li & Zhihao Chen & Aijaz A. John & Qiang Qiu & Lihua Julie Zhu & Matthew B. Gre, 2022. "Impaired mitochondrial oxidative metabolism in skeletal progenitor cells leads to musculoskeletal disintegration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    17. Zaher ElBeck & Mohammad Bakhtiar Hossain & Humam Siga & Nikolay Oskolkov & Fredrik Karlsson & Julia Lindgren & Anna Walentinsson & Dominique Koppenhöfer & Rebecca Jarvis & Roland Bürli & Tanguy Jamier, 2024. "Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    18. Wennan Zhao & Xue Wang & Lifeng Han & Chunze Zhang & Chenxi Wang & Dexin Kong & Mingzhe Zhang & Tong Xu & Gen Li & Ge Hu & Jiahua Luo & Sook Wah Yee & Jia Yang & Andreas Stahl & Xin Chen & Youcai Zhan, 2024. "SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    19. Le Tran Phuc Khoa & Wentao Yang & Mengrou Shan & Li Zhang & Fengbiao Mao & Bo Zhou & Qiang Li & Rebecca Malcore & Clair Harris & Lili Zhao & Rajesh C. Rao & Shigeki Iwase & Sundeep Kalantry & Stephani, 2024. "Quiescence enables unrestricted cell fate in naive embryonic stem cells," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    20. Ryann M. Fame & Peter N. Kalugin & Boryana Petrova & Huixin Xu & Paul A. Soden & Frederick B. Shipley & Neil Dani & Bradford Grant & Aja Pragana & Joshua P. Head & Suhasini Gupta & Morgan L. Shannon &, 2023. "Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29639-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.