Glutamine Metabolism Mediates Sensitivity to Respiratory Complex II Inhibition in Acute Myeloid Leukemia Academic Article uri icon

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abstract

  • Abstract Acute myeloid leukemia (AML) is a hematologic malignancy metabolically dependent on oxidative phosphorylation and mitochondrial electron transport chain (ETC) activity. AML cells are distinct from their normal hematopoietic counterparts by this metabolic reprogramming, which presents targets for new selective therapies. Here, metabolic changes in AML cells after ETC impairment are investigated. Genetic knockdown of the ETC complex II (CII) chaperone protein SDHAF1 (succinate dehydrogenase assembly factor 1) suppressed CII activity and delayed AML cell growth in vitro and in vivo. As a result, a novel small molecule that directly binds to the ubiquinone binding site of CII and inhibits its activity was identified. Pharmacologic inhibition of CII induced selective death of AML cells while sparing normal hematopoietic progenitors. Through stable isotope tracing, results show that genetic or pharmacologic inhibition of CII truncates the tricarboxylic acid cycle (TCA) and leads to anaplerotic glutamine metabolism to reestablish the truncated cycle. The inhibition of CII showed divergent fates, as AML cells lacked the metabolic plasticity to adequately utilize glutamine metabolism, resulting in preferential depletion of key TCA metabolites and death; normal cells were unaffected. These findings provide insight into the metabolic mechanisms that underlie AML's selective inhibition of CII. Implications: This work highlights the effects of direct CII inhibition in mediating selective AML cell death and provides insights into glutamine anaplerosis as a metabolic adaptation that can be therapeutically targeted.

authors

  • Roma, Alessia
  • Tcheng, Matthew
  • Ahmed, Nawaz
  • Walker, Sarah
  • Jayanth, Preethi
  • Minden, Mark D
  • Hope, Kristin
  • Nekkar Rao, Praveen P
  • Luc, Jessica
  • Doxey, Andrew
  • Reisz, Julie A
  • Culp-Hill, Rachel
  • D'Alessandro, Angelo
  • Spagnuolo, Paul A

publication date

  • November 3, 2022