Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal

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.