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- Title
The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability.
- Authors
Mirali, Sara; Botham, Aaron; Voisin, Veronique; Xu, Changjiang; St-Germain, Jonathan; Sharon, David; Hoff, Fieke W.; Qiu, Yihua; Hurren, Rose; Gronda, Marcela; Jitkova, Yulia; Nachmias, Boaz; MacLean, Neil; Wang, Xiaoming; Arruda, Andrea; Minden, Mark D.; Horton, Terzah M.; Kornblau, Steven M.; Chan, Steven M.; Bader, Gary D.
- Abstract
Cutting leukemia's energy supply: Neurolysin is a protein that is found in the mitochondria and secreted into the circulation. It is known to help regulate physiological functions such as blood pressure but is not essential for survival in mice. Mirali et al. discovered that neurolysin is frequently overexpressed in acute myeloid leukemia. The authors examined the underlying mechanism and identified the role of neurolysin in the formation of respiratory chain supercomplexes in the mitochondria. They also showed that inhibition of neurolysin is selectively toxic to leukemic cells without affecting normal hematopoietic cells and demonstrated the effectiveness of this approach in mouse models of leukemia. 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.
- Subjects
ACUTE myeloid leukemia; STEM cells; PEPTIDASE; POWER resources; BLOOD pressure; HEMATOPOIETIC growth factors
- Publication
Science Translational Medicine, 2020, Vol 12, Issue 538, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aaz8264