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 - 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.
UR - http://www.scopus.com/inward/record.url?scp=85117220347&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s42255-021-00471-y
DO - https://doi.org/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 -