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December 8, 2025Blood

F1 subunit-specific ATP synthase inhibition disrupts AML mitochondrial metabolism distinctly from other electron transport chain inhibitors

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Authors

MVMatthew T. VillaumeSTStefano TizianiMSMichael R. Savona

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Overview

Preclinical evaluation reveals ATP synthase inhibition lowers cell viability in AML, suggesting unique metabolic pathways.

Key Points

  • This research aims to evaluate the effects of selective F1 inhibition on mitochondrial metabolism in acute myeloid leukemia (AML).
  • Analyzed AML cell lines with various OXPHOS inhibitors
  • Utilized mass spectrometry to assess metabolic changes
  • Conducted Seahorse XF analysis for oxygen consumption rates
  • Performed flow cytometry for cell cycle and viability measurements
  • Examined mitochondrial morphology via Tunneling EM
  • EB2023, a selective F1 inhibitor, induced more cell death compared to IACS-010759 in AML cell lines
  • IACS treatment caused rapid mitochondrial ROS accumulation and NAD+ depletion, contrasting with EB2023 and oligomycin
  • EB2023 treatment preserved the ADP/ATP ratio better than other inhibitors
  • Only EB2023 showed significant mitochondrial morphological changes, indicating severe stress
  • Metabolomic assays demonstrated distinct metabolic pathways activated by different inhibitors.

Cite This Study

Villaume et al. (2025) studied this question.

synapsesocial.com/papers/69362f6c4fa91c937236df9ehttps://doi.org/10.1182/blood-2025-6103
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