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

Abstract Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here, we reveal glutaminase (Gls) 1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis. In addition, impaired macrophage glutaminolysis exacerbated atherosclerosis, a condition during which efficient apoptotic cell debris clearance is critical to limit disease progression. Gls1 expression strongly correlated with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling revealed that macrophage efferocytic capacity rely on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase (Glud1) to fuel ɑ-ketogulatrate-dependent immunometabolism. This pathway was necessary to meet the unique requirements of efferocytosis for cellular detoxification and high energy cytoskeletal rearrangements. Thus, we uncovered a novel role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease.