The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability.
Sara MiraliAaron BothamVeronique VoisinChangjiang XuJonathan R St-GermainDavid SharonFieke W HoffYihua QiuRose HurrenMarcela GrondaYulia JitkovaBoaz NachmiasNeil MacLeanXiaoming WangAndrea ArrudaMark D MindenTerzah M HortonSteven Mitchell KornblauSteven M ChanGary D BaiderBrian RaughtAaron David SchimmerPublished in: Science translational medicine (2021)
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.
Keyphrases
- acute myeloid leukemia
- stem cells
- induced apoptosis
- allogeneic hematopoietic stem cell transplantation
- cell cycle arrest
- oxidative stress
- signaling pathway
- endoplasmic reticulum stress
- bone marrow
- transcription factor
- cell proliferation
- drug delivery
- pi k akt
- gene expression
- respiratory tract
- resting state
- minimally invasive