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

doi:10.1038/s41467-022-29639-0

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

Nat Commun. 2022 Apr 19;13(1):2013. doi: 10.1038/s41467-022-29639-0.

Authors

Ayşegül Erdem^{1

2}, Silvia Marin^{2

3

4}, Diego A Pereira-Martins^{1

5}, Marjan Geugien¹, Alan Cunningham¹, Maurien G Pruis¹, Isabel Weinhäuser^{1

5}, Albert Gerding^{6

7}, Barbara M Bakker⁷, Albertus T J Wierenga^{1

6}, Eduardo M Rego⁵, Gerwin Huls¹, Marta Cascante^{2

3

4}, Jan Jacob Schuringa⁸

Affiliations

¹ Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
² Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Avda. Diagonal 643, Barcelona, 08028, Spain.
³ CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III, 28029, Madrid, Spain.
⁴ Institute of Biomedicine of University of Barcelona, 08028, Barcelona, Spain.
⁵ Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo, São Paulo, SP, Brazil.
⁶ Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
⁷ Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁸ Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Lactic Acid
Oxidoreductases
fms-Like Tyrosine Kinase 3