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

Published in:

Authors: 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

Summary

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.

Link to Pubmed [PMID] – 34650273

Link to DOI – 10.1038/s42255-021-00471-y