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)

1 C3M - Centre méditerranéen de médecine moléculaire
2 OncoAge - FHU OncoAge - Pathologies liées à l’âge [CHU Nice]
3 ITMO University [Russia]
4 Washington University School of Medicine [Saint Louis, MO]
5 CCMA - Centre Commun de Microscopie Appliquée [Nice]
6 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
7 UNIGE - Université de Genève = University of Geneva
8 The Wellcome Trust Sanger Institute [Cambridge]
9 CAM - University of Cambridge [UK]
10 IFM - Inserm U1270 - SU - Institut du Fer à Moulin
11 NYSPI - The New York State Psychiatric Institute
12 Columbia University [New York]
13 University of Haifa [Haifa]
14 MUMC - Maastricht University Medical Centre
15 RWTH - Rheinisch-Westfälische Technische Hochschule Aachen University
16 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
17 Northwestern University [Chicago, Ill. USA]

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.

Domains: Life Sciences [q-bio]

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, 2021, 3 (10), pp.1313-1326. ⟨10.1038/s42255-021-00471-y⟩. ⟨hal-03798344⟩