The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability
- 8 April 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (538)
- https://doi.org/10.1126/scitranslmed.aaz8264
Abstract
Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function is unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition of NLN was selectively cytotoxic to AML cells and stem cells while sparing normal hematopoietic cells. Mechanistically, NLN interacted with the mitochondrial respiratory chain. Genetic and chemical inhibition of NLN impaired oxidative metabolism and disrupted the formation of respiratory chain supercomplexes (RCS). Furthermore, NLN interacted with the known RCS regulator, LETM1, and inhibition of NLN disrupted LETM1 complex formation. RCS were increased in patients with AML and positively correlated with NLN expression. These findings demonstrate that inhibiting RCS formation selectively targets AML cells and stem cells and highlights the therapeutic potential of pharmacologically targeting NLN in AML.Funding Information
- National Institutes of Health (R01-CA164024)
- Princess Margaret Cancer Foundation
- Ontario Institute for Cancer Research
- Canadian Cancer Society Research Institute
- Canadian Institutes of Health Research
- Ontario Ministry of Health and Long-Term Care
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