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

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

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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
Pages (from-to)	1313-1326
Number of pages	29
Journal	Nature Metabolism
Volume	3
Issue number	10
Early online date	14 Oct 2021
DOIs	https://doi.org/10.1038/s42255-021-00471-y
Publication status	Published - Oct 2021

Keywords

ELECTRON-TRANSPORT
CELL
METABOLISM
MITOCHONDRIA
EXPRESSION
PROMOTES
MOUSE

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10.1038/s42255-021-00471-y

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Cite this

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.",

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doi = "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, 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.

KW - ELECTRON-TRANSPORT

KW - CELL

KW - METABOLISM

KW - MITOCHONDRIA

KW - EXPRESSION

KW - PROMOTES

KW - MOUSE

U2 - 10.1038/s42255-021-00471-y

DO - 10.1038/s42255-021-00471-y

M3 - Article

C2 - 34650273

SN - 2522-5812

VL - 3

SP - 1313

EP - 1326

JO - Nature Metabolism

JF - Nature Metabolism

IS - 10

ER -