Skip to Content
MilliporeSigma
  • Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal.

Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal.

Cell stem cell (2020-05-18)
Rashim Pal Singh, Danny V Jeyaraju, Veronique Voisin, Rose Hurren, Changjiang Xu, James R Hawley, Samir H Barghout, Dilshad H Khan, Marcela Gronda, Xiaoming Wang, Yulia Jitkova, David Sharon, Sanduni Liyanagae, Neil MacLean, Ayesh K Seneviratene, Sara Mirali, Adina Borenstein, Geethu E Thomas, Joelle Soriano, Elias Orouji, Mark D Minden, Andrea Arruda, Steven M Chan, Gary D Bader, Mathieu Lupien, Aaron D Schimmer
ABSTRACT

Leukemic stem cells (LSCs) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins is folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal, and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone, and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-adenosylhomocysteine hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Bovine Serum Albumin, heat shock fraction, pH 7, ≥98%
Sigma-Aldrich
Puromycin dihydrochloride from Streptomyces alboniger, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Anti-Dynamin related protein 1 (Drp1) Antibody, from rabbit, purified by affinity chromatography
Sigma-Aldrich
D-Penicillamine, 98-101%
Sigma-Aldrich
Triton X-100, laboratory grade
Millipore
Immobilon®-FL PVDF Membrane, 1 roll, 27 cm x 3.75 m, 0.45 µm pore size, Hydrophobic PVDF Transfer Membrane with low background fluorescence for Western blotting. Compatible with visible and infrared fluorescent probes.
Millipore
Immobilon®-PSQ PVDF Membrane, 1 roll, 27 cm x 3.75 m, 0.2 µm pore size, Hydrophobic PVDF Transfer Membrane for western blotting.