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. Bader; Brian Raught; Aaron D. Schimmer

doi:10.1126/scitranslmed.aaz8264

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

Leukemia

Research output: Contribution to journal › Article › peer-review

34 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 language	English (US)
Article number	eaaz8264
Journal	Science translational medicine
Volume	12
Issue number	538
DOIs	https://doi.org/10.1126/scitranslmed.aaz8264
State	Published - Apr 8 2020

ASJC Scopus subject areas

General Medicine

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10.1126/scitranslmed.aaz8264

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Mirali, S., Botham, A., Voisin, V., Xu, C., St-Germain, J., Sharon, D., Hoff, F. W., Qiu, Y., Hurren, R., Gronda, M., Jitkova, Y., Nachmias, B., MacLean, N., Wang, X., Arruda, A., Minden, M. D., Horton, T. M., Kornblau, S. M., Chan, S. M., ... Schimmer, A. D. (2020). The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability. Science translational medicine, 12(538), Article eaaz8264. https://doi.org/10.1126/scitranslmed.aaz8264

Mirali, S, Botham, A, Voisin, V, Xu, C, St-Germain, J, Sharon, D, Hoff, FW, Qiu, Y, Hurren, R, Gronda, M, Jitkova, Y, Nachmias, B, MacLean, N, Wang, X, Arruda, A, Minden, MD, Horton, TM, Kornblau, SM, Chan, SM, Bader, GD, Raught, B & Schimmer, AD 2020, 'The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability', Science translational medicine, vol. 12, no. 538, eaaz8264. https://doi.org/10.1126/scitranslmed.aaz8264

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

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.",

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

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doi = "10.1126/scitranslmed.aaz8264",

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T1 - The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability

AU - Mirali, Sara

AU - Botham, Aaron

AU - Voisin, Veronique

AU - Xu, Changjiang

AU - St-Germain, Jonathan

AU - Sharon, David

AU - Hoff, Fieke W.

AU - Qiu, Yihua

AU - Hurren, Rose

AU - Gronda, Marcela

AU - Jitkova, Yulia

AU - Nachmias, Boaz

AU - MacLean, Neil

AU - Wang, Xiaoming

AU - Arruda, Andrea

AU - Minden, Mark D.

AU - Horton, Terzah M.

AU - Kornblau, Steven M.

AU - Chan, Steven M.

AU - Bader, Gary D.

AU - Raught, Brian

AU - Schimmer, Aaron D.

PY - 2020/4/8

Y1 - 2020/4/8

N2 - 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.

AB - 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.

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

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