The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability

Sara Mirali, Aaron Botham, Veronique Voisin, Changjiang Xu, Jonathan St-Germain, David Sharon, Fieke W. Hoff, Yihua Qiu, Rose Hurren, Marcela Gronda, Yulia Jitkova, Boaz Nachmias, Neil MacLean, Xiaoming Wang, Andrea Arruda, Mark D. Minden, Terzah M. Horton, Steven M. Kornblau, Steven M. Chan, Gary D. BaderBrian Raught, Aaron D. Schimmer

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish
Article numbereaaz8264
JournalScience Translational Medicine
Volume12
Issue number538
DOIs
StatePublished - 8 Apr 2020
Externally publishedYes

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