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Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation
Nature Metabolism ( IF 20.8 ) Pub Date : 2021-10-14 , DOI: 10.1038/s42255-021-00471-y
Johanna Merlin 1 , Stoyan Ivanov 1 , Adélie Dumont 1 , Alexey Sergushichev 2 , Julie Gall 1 , Marion Stunault 1 , Marion Ayrault 1 , Nathalie Vaillant 1 , Alexia Castiglione 1 , Amanda Swain 3 , Francois Orange 4 , Alexandre Gallerand 1 , Thierry Berton 5 , Jean-Charles Martin 5 , Stefania Carobbio 6, 7, 8 , Justine Masson 9, 10 , Inna Gaisler-Salomon 10, 11, 12 , Pierre Maechler 6 , Stephen Rayport 10, 11 , Judith C Sluimer 13 , Erik A L Biessen 13, 14 , Rodolphe R Guinamard 1 , Emmanuel L Gautier 15 , Edward B Thorp 16 , Maxim N Artyomov 3 , Laurent Yvan-Charvet 1
Affiliation  

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.



中文翻译:

非经典谷氨酰胺转氨作用通过将氧化还原缓冲与氧化磷酸化耦合来维持胞吞作用

巨噬细胞依靠紧密整合的代谢重连,在稳态和疾病期间通过胞吞作用清除濒临死亡的细胞。在这里,我们揭示了谷氨酰胺酶 1 介导的谷氨酰胺分解对于小鼠体内稳态期间促进巨噬细胞清除凋亡细胞至关重要。此外,巨噬细胞谷氨酰胺分解受损会加剧动脉粥样硬化,在这种情况下,有效的凋亡细胞碎片清除对于限制疾病进展至关重要。谷氨酰胺酶-1 表达与心血管疾病患者的动脉粥样硬化斑块坏死密切相关。高通量转录和代谢分析表明,巨噬细胞的胞吞能力依赖于非典型转氨酶途径,独立于谷氨酸脱氢酶来促进 ɑ-酮戊二酸依赖性免疫代谢的传统需求。该途径对于满足细胞解毒和高能细胞骨架重排的胞吞作用的独特要求是必要的。因此,我们发现了非典型谷氨酰胺代谢在小鼠和人类健康和疾病期间有效清除垂死细胞和维持组织稳态的作用。

更新日期:2021-10-14
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