Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival
Abstract Background Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA),...
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BMC
2025-05-01
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| Series: | Cancer & Metabolism |
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| Online Access: | https://doi.org/10.1186/s40170-025-00392-4 |
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| author | Ayşegül Erdem Séléna Kaye Francesco Caligiore Manuel Johanns Fleur Leguay Jan Jacob Schuringa Keisuke Ito Guido Bommer Nick van Gastel |
| author_facet | Ayşegül Erdem Séléna Kaye Francesco Caligiore Manuel Johanns Fleur Leguay Jan Jacob Schuringa Keisuke Ito Guido Bommer Nick van Gastel |
| author_sort | Ayşegül Erdem |
| collection | DOAJ |
| description | Abstract Background Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+. Methods We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry. Results Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition. Conclusions Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells. |
| format | Article |
| id | doaj-art-822a6d2e26a040eaba7a5989318637d0 |
| institution | OA Journals |
| issn | 2049-3002 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| spelling | doaj-art-822a6d2e26a040eaba7a5989318637d02025-08-20T01:53:25ZengBMCCancer & Metabolism2049-30022025-05-0113111610.1186/s40170-025-00392-4Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survivalAyşegül Erdem0Séléna Kaye1Francesco Caligiore2Manuel Johanns3Fleur Leguay4Jan Jacob Schuringa5Keisuke Ito6Guido Bommer7Nick van Gastel8Cellular Metabolism and Microenvironment Laboratory, de Duve Institute, UCLouvainCellular Metabolism and Microenvironment Laboratory, de Duve Institute, UCLouvainBiochemistry and Metabolic Research Group, de Duve Institute, UCLouvainProtein Phosphorylation Group, de Duve Institute, UCLouvainCellular Metabolism and Microenvironment Laboratory, de Duve Institute, UCLouvainDepartment of Experimental Hematology, University Medical Center Groningen, University of GroningenRuth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of MedicineBiochemistry and Metabolic Research Group, de Duve Institute, UCLouvainCellular Metabolism and Microenvironment Laboratory, de Duve Institute, UCLouvainAbstract Background Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+. Methods We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry. Results Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition. Conclusions Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.https://doi.org/10.1186/s40170-025-00392-4Cancer metabolismAcute myeloid leukemiaGlycolysisLactate dehydrogenase ARedox balanceNAD+ |
| spellingShingle | Ayşegül Erdem Séléna Kaye Francesco Caligiore Manuel Johanns Fleur Leguay Jan Jacob Schuringa Keisuke Ito Guido Bommer Nick van Gastel Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival Cancer & Metabolism Cancer metabolism Acute myeloid leukemia Glycolysis Lactate dehydrogenase A Redox balance NAD+ |
| title | Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival |
| title_full | Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival |
| title_fullStr | Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival |
| title_full_unstemmed | Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival |
| title_short | Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival |
| title_sort | lactate dehydrogenase a coupled nad regeneration is critical for acute myeloid leukemia cell survival |
| topic | Cancer metabolism Acute myeloid leukemia Glycolysis Lactate dehydrogenase A Redox balance NAD+ |
| url | https://doi.org/10.1186/s40170-025-00392-4 |
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