Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation

Johanna Merlin; Stoyan Ivanov; Adélie Dumont; Alexey Sergushichev; Julie Gall; Marion Stunault; Marion Ayrault; Nathalie Vaillant; Alexia Castiglione; Amanda Swain; Francois Orange; Alexandre Gallerand; Thierry Berton; Jean Charles Martin; Stefania Carobbio; Justine Masson; Inna Gaisler-Salomon; Pierre Maechler; Stephen Rayport; Judith C. Sluimer; Erik A.L. Biessen; Rodolphe R. Guinamard; Emmanuel L. Gautier; Edward B. Thorp; Maxim N. Artyomov; Laurent Yvan-Charvet

doi:10.1038/s42255-021-00471-y

Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation

Johanna Merlin, Stoyan Ivanov, Adélie Dumont, Alexey Sergushichev, Julie Gall, Marion Stunault, Marion Ayrault, Nathalie Vaillant, Alexia Castiglione, Amanda Swain, Francois Orange, Alexandre Gallerand, Thierry Berton, Jean Charles Martin, Stefania Carobbio, Justine Masson, Inna Gaisler-Salomon, Pierre Maechler, Stephen Rayport, Judith C. SluimerErik A.L. Biessen, Rodolphe R. Guinamard, Emmanuel L. Gautier, Edward B. Thorp, Maxim N. Artyomov, Laurent Yvan-Charvet^*

^*Corresponding author for this work

Pathology

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

50 Scopus citations

Abstract

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans.

Original language	English (US)
Pages (from-to)	1313-1326
Number of pages	14
Journal	Nature Metabolism
Volume	3
Issue number	10
DOIs	https://doi.org/10.1038/s42255-021-00471-y
State	Published - Oct 2021

Funding

We thank B. Caraveo for computional development of DreamBio, a new topological tool for Integrated Network Analysis. N. Grandchamp provided Lenti-ONE AOX vector through GEG Tech. We thank S. Fernandez for the noninvasive study of atheroma plaques by ultrasound echography as part of the European Center for Research in Imaging (Cerimed), F. Labret for assistance with flow cytometry, V. Corcelle for assistance in animal facilities and M. Irondelle for assistance with confocal microscopy. This work was supported by grants from the Fondation de France, ANR and the European Research Council consolidator program (ERC2016COG724838) to L.Y.-C. CCMA electron microscopy equipment was funded by the R\u00E9gion Sud - Provence-Alpes-C\u00F4te d\u2019Azur, the Conseil D\u00E9partemental des Alpes Maritimes and the GIS-IBiSA.

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Physiology (medical)
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s42255-021-00471-y

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Merlin, J., Ivanov, S., Dumont, A., Sergushichev, A., Gall, J., Stunault, M., Ayrault, M., Vaillant, N., Castiglione, A., Swain, A., Orange, F., Gallerand, A., Berton, T., Martin, J. C., Carobbio, S., Masson, J., Gaisler-Salomon, I., Maechler, P., Rayport, S., ... Yvan-Charvet, L. (2021). Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation. Nature Metabolism, 3(10), 1313-1326. https://doi.org/10.1038/s42255-021-00471-y

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title = "Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation",

abstract = "Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans.",

author = "Johanna Merlin and Stoyan Ivanov and Ad{\'e}lie Dumont and Alexey Sergushichev and Julie Gall and Marion Stunault and Marion Ayrault and Nathalie Vaillant and Alexia Castiglione and Amanda Swain and Francois Orange and Alexandre Gallerand and Thierry Berton and Martin, {Jean Charles} and Stefania Carobbio and Justine Masson and Inna Gaisler-Salomon and Pierre Maechler and Stephen Rayport and Sluimer, {Judith C.} and Biessen, {Erik A.L.} and Guinamard, {Rodolphe R.} and Gautier, {Emmanuel L.} and Thorp, {Edward B.} and Artyomov, {Maxim N.} and Laurent Yvan-Charvet",

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year = "2021",

month = oct,

doi = "10.1038/s42255-021-00471-y",

language = "English (US)",

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Merlin, J, Ivanov, S, Dumont, A, Sergushichev, A, Gall, J, Stunault, M, Ayrault, M, Vaillant, N, Castiglione, A, Swain, A, Orange, F, Gallerand, A, Berton, T, Martin, JC, Carobbio, S, Masson, J, Gaisler-Salomon, I, Maechler, P, Rayport, S, Sluimer, JC, Biessen, EAL, Guinamard, RR, Gautier, EL, Thorp, EB, Artyomov, MN & Yvan-Charvet, L 2021, 'Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation', Nature Metabolism, vol. 3, no. 10, pp. 1313-1326. https://doi.org/10.1038/s42255-021-00471-y

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T1 - Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation

AU - Merlin, Johanna

AU - Ivanov, Stoyan

AU - Dumont, Adélie

AU - Sergushichev, Alexey

AU - Gall, Julie

AU - Stunault, Marion

AU - Ayrault, Marion

AU - Vaillant, Nathalie

AU - Castiglione, Alexia

AU - Swain, Amanda

AU - Orange, Francois

AU - Gallerand, Alexandre

AU - Berton, Thierry

AU - Martin, Jean Charles

AU - Carobbio, Stefania

AU - Masson, Justine

AU - Gaisler-Salomon, Inna

AU - Maechler, Pierre

AU - Rayport, Stephen

AU - Sluimer, Judith C.

AU - Biessen, Erik A.L.

AU - Guinamard, Rodolphe R.

AU - Gautier, Emmanuel L.

AU - Thorp, Edward B.

AU - Artyomov, Maxim N.

AU - Yvan-Charvet, Laurent

PY - 2021/10

Y1 - 2021/10

N2 - Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans.

AB - Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans.

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JO - Nature Metabolism

JF - Nature Metabolism

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ER -

Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation

Abstract

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