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Updated: Dec 21, 2025

Improving the Accuracy of Flow Cytometric Assessment of Mitochondrial Membrane Potential in Hematopoietic Stem and Progenitor Cells Through the Inhibition of Efflux Pumps
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Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal

Rashim Pal Singh1, Danny V Jeyaraju1, Veronique Voisin2

  • 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Cell Stem Cell
|May 17, 2020
PubMed

Insights

Targeting the mitochondrial intermembrane assembly (MIA) pathway in acute myeloid leukemia (AML) stem cells disrupts their growth and self-renewal. Inhibiting this pathway, specifically ALR and COX17, lowers viability by altering epigenetic status.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) depend on oxidative metabolism.
  • Mitochondrial pathways, including the mitochondrial intermembrane assembly (MIA) pathway, are potential therapeutic targets.
  • The MIA pathway is crucial for folding specific mitochondrial proteins.

Purpose of the Study:

  • To investigate the role of the MIA pathway in AML stem cells.
  • To evaluate the therapeutic potential of inhibiting the MIA pathway in AML.

Main Methods:

  • Analysis of MIA pathway substrate mRNA expression in AML stem cells.
  • Genetic and chemical inhibition of the MIA pathway component ALR (amino-acid-racemase).
  • Knockdown of COX17, a substrate of ALR and mitochondrial copper chaperone.
  • Measurement of mitochondrial copper levels, S-adenosylhomocysteine hydrolase (SAHH) activity, and S-adenosylmethionine (SAM) levels.
  • Assessment of DNA methylation and chromatin accessibility.

Main Results:

  • Increased mRNA expression of MIA pathway substrates was observed in AML stem cells.
  • Inhibition of ALR reduced AML growth, viability, LSC self-renewal, and induced differentiation.
  • ALR inhibition decreased COX17 levels, and COX17 knockdown mimicked ALR inhibition effects.
  • Inhibition of ALR and COX17 led to increased mitochondrial copper, decreased SAHH activity, and reduced SAM levels.
  • These changes resulted in decreased DNA methylation and altered chromatin accessibility, lowering LSC viability.

Conclusions:

  • The MIA pathway is a critical regulator of AML stem cell viability.
  • Inhibiting ALR and its substrate COX17 offers a potential therapeutic strategy for AML.
  • Mitochondrial copper accumulation disrupts epigenetic regulation (DNA methylation) and chromatin accessibility, leading to LSC death.
Keywords:
ALRAMLCOX17LSCscopper

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