加拿大大学健康网络Aaron D. Schimmer研究小组发现，破坏线粒体铜离子分布能够抑制白血病干细胞的自我更新。相关论文2020年5月15日在线发表于《细胞—干细胞》。

Title: Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal

Author: 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

Issue&Volume: 2020-05-15

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

DOI: 10.1016/j.stem.2020.04.010

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30149-1