1. Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal
- Author
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Mark D. Minden, Neil MacLean, Steven M. Chan, Sanduni Liyanagae, Sara Mirali, Changjiang Xu, James R. Hawley, Samir H. Barghout, Rashim Pal Singh, Elias Orouji, Aaron D. Schimmer, Xiaoming Wang, Gary D. Bader, Marcela Gronda, Dilshad H. Khan, Joelle Soriano, Mathieu Lupien, Veronique Voisin, Yulia Jitkova, Danny V. Jeyaraju, Geethu E. Thomas, David Sharon, Adina Borenstein, Rose Hurren, Ayesh K. Seneviratene, and Andrea Arruda
- Subjects
0303 health sciences ,Gene knockdown ,biology ,Cell Differentiation ,Cell Biology ,Chromatin ,Cell biology ,Leukemia, Myeloid, Acute ,03 medical and health sciences ,Haematopoiesis ,0302 clinical medicine ,COX17 ,Chaperone (protein) ,DNA methylation ,Neoplastic Stem Cells ,Genetics ,biology.protein ,Humans ,Molecular Medicine ,Cell Self Renewal ,Stem cell ,Intermembrane space ,Copper ,030217 neurology & neurosurgery ,030304 developmental biology - 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.
- Published
- 2020
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