TY - JOUR
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
N1 - Funding Information:
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 Région Sud - Provence-Alpes-Côte d’Azur, the Conseil Départemental des Alpes Maritimes and the GIS-IBiSA.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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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U2 - 10.1038/s42255-021-00471-y
DO - 10.1038/s42255-021-00471-y
M3 - Article
C2 - 34650273
AN - SCOPUS:85117220347
SN - 2522-5812
VL - 3
SP - 1313
EP - 1326
JO - Nature Metabolism
JF - Nature Metabolism
IS - 10
ER -
