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

Johanna Merlin 1, 2 Stoyan Ivanov 1, 2 Adélie Dumont 1, 2 Alexey Sergushichev 3 Julie Gall 1, 2 Marion Stunault 1, 2 Marion Ayrault 1, 2 Nathalie Vaillant 1, 2 Alexia Castiglione 1, 2 Amanda Swain 4 Francois Orange 5 Alexandre Gallerand 1, 2 Thierry Berton 6 Jean-Charles Martin 6 Stefania Carobbio 7, 8, 9 Justine Masson 10, 11 Inna Gaisler-Salomon 11, 12, 13 Pierre Maechler 7 Stephen Rayport 11, 12 Judith Sluimer 14 Erik Biessen 14, 15 Rodolphe Guinamard 1, 2 Emmanuel Gautier 16 Edward Thorp 17 Maxim Artyomov 4 Laurent yvan-Charvet 1, 2 
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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https://hal-amu.archives-ouvertes.fr/hal-03653344
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Submitted on : Wednesday, April 27, 2022 - 4:24:58 PM
Last modification on : Friday, May 20, 2022 - 11:06:56 AM

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Johanna Merlin, Stoyan Ivanov, Adélie Dumont, Alexey Sergushichev, Julie Gall, et al.. Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation. Nature Metabolism, Nature Publishing Group, 2021, 3 (10), pp.1313-1326. ⟨10.1038/s42255-021-00471-y⟩. ⟨hal-03653344⟩

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