美国梅奥诊所医学与科学学院 Cornelia M. Weyand 研究小组发现，线粒体天冬氨酸能够调节肿瘤坏死因子（TNF）的生物合成和自身免疫组织炎症。这一研究成果于2021年11月22日在线发表在《自然—免疫学》杂志上。

研究人员指出，在类风湿关节炎患者的T细胞中，线粒体天冬氨酸的合成不足。线粒体天冬氨酸的短缺破坏了代谢辅因子烟酰胺腺嘌呤二核苷酸的再生，导致内质网 (ER) 传感器 GRP78/BiP 的 ADP 去核糖基化。最终引起富含核糖体的 ER 膜膨胀扩张，从而促进共翻译转运并增强跨膜 TNF 的生物合成。 ER^rich T 细胞是关节炎关节中TNF的主要生产者。若将完整的线粒体转移到 T 细胞中，或者是补充外源性天冬氨酸，都能够抑制线粒体驱动的 ER 膜扩张从而阻断TNF的释放以及类风湿组织炎症的发生。

据了解，错误指导的免疫会引起类风湿性关节炎的自身免疫性组织炎症，其中致病的关键因素在于肿瘤坏死因子（TNF）的过量产生。虽然这种自我耐受机制损坏的潜在原因还不清楚，但是目前已经发现在有关节炎关节中的T细胞具有独特的ATP^lo acetyl-CoA^hi促炎效应细胞的代谢特征。

附：英文原文

Title: Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation

Author: Wu, Bowen, Zhao, Tuantuan V., Jin, Ke, Hu, Zhaolan, Abdel, Matthew P., Warrington, Ken J., Goronzy, Jrg J., Weyand, Cornelia M.

Issue&Volume: 2021-11-22

Abstract: Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation. Mitochondrial aspartate regulates ER morphology and co-translational translocation via BiP ADP ribosylation. In T cells from patients with rheumatoid arthritis, mitochondrial aspartate is deficient, resulting in ER expansion and excessive production of the pro-inflammatory cytokine TNF.

DOI: 10.1038/s41590-021-01065-2

Source: https://www.nature.com/articles/s41590-021-01065-2