The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons de leucémie myéloïde aiguë obtenus à partir du sang périphérique ou de la moelle osseuse de patients, cette étude met en évidence le rôle de la neurolysine, une peptidase mitochondriale, dans la régulation de la formation du super complexe protéique de la chaîne respiratoire et la viabilité des cellules leucémiques
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.