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Merlin J, Ivanov S, Dumont A, et al. Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation. Nat Metab. 2021;3(10):1313-1326doi: 10.1038/s42255-021-00471-y.
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, J. C., Biessen, E. A. L., Guinamard, R. R., Gautier, E. L., Thorp, E. B., Artyomov, M. N., & 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
Merlin, Johanna, et al. "Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation." Nature metabolism vol. 3,10 (2021): 1313-1326. doi: https://doi.org/10.1038/s42255-021-00471-y
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 JC, 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. Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation. Nat Metab. 2021 Oct;3(10):1313-1326. doi: 10.1038/s42255-021-00471-y. Epub 2021 Oct 14. PMID: 34650273; PMCID: PMC7611882.
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Nat Metab. 2021 Oct;3(10):1313-1326. doi: 10.1038/s42255-021-00471-y. Epub 2021 Oct 14.

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

Nature metabolism

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

Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Centre National de la Recherche Scientifique (CNRS) (R.G.), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France.
  2. Computer Technologies Department, ITMO University, Saint Petersburg, Russia.
  3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  4. Université Côte d'Azur, Centre Commun de Microscopie Appliquée (CCMA), Nice, France.
  5. Centre de Recherche Cardiovasculaire et Nutritionnelle (C2VN), INSERM, Institut National de la Recherche Agricole (INRA), BioMet, Aix-Marseille University, Marseille, France.
  6. Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, Geneva, Switzerland.
  7. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
  8. Metabolic Research Laboratories, Addenbrooke's Treatment Centre, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
  9. Inserm UMR-S1270, Institut du Fer à Moulin, Sorbonne Université, Paris, France.
  10. Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, NY, USA.
  11. Department of Psychiatry, Columbia University, New York, NY, USA.
  12. SPC-IBBR, University of Haifa, Haifa, Israel.
  13. Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands.
  14. Institute for Molecular Cardiovascular Research, RWTH Klinikum Aachen, Aachen, Germany.
  15. Sorbonne Université, INSERM, UMR_S 1166 ICAN, Paris, France.
  16. Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
  17. Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Centre National de la Recherche Scientifique (CNRS) (R.G.), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France. [email protected].

PMID: 34650273 PMCID: PMC7611882 DOI: 10.1038/s42255-021-00471-y

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.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

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