近日，中国医学科学院黄波课题组发现，氨诱导的溶酶体和线粒体损伤导致效应CD8⁺ T细胞死亡。该研究于2024年9月11日在线发表于国际一流学术期刊《自然—细胞生物学》。

研究人员发现氨会引发效应T细胞的一种独特的细胞死亡形式。研究表明，快速增殖的T细胞通过谷氨酰胺分解作用在线粒体中释放氨，氨随后被转运至溶酶体并储存。

过量的氨积累会增加溶酶体的pH值，导致溶酶体氨存储终止，氨反流回线粒体，进而引发线粒体损伤和细胞死亡。

这一过程表现为溶酶体碱化、线粒体肿胀和自噬流受损。抑制谷氨酰胺分解或阻止溶酶体碱化可以防止氨诱导的T细胞死亡，并改善基于T细胞的抗肿瘤免疫疗法。这些发现揭示了一种不同于已知机制的独特细胞死亡形式。

研究人员表示，氨被认为是一种细胞毒素，其在血液中的增加会损害细胞功能。然而，该毒素是否以及如何在病理生理条件下触发细胞死亡仍不清楚。

附：英文原文

Title: Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells

Author: Zhang, Huafeng, Liu, Jincheng, Yuan, Wu, Zhang, Qian, Luo, Xiao, Li, Yonggang, Peng, Yuee, Feng, Jingyu, Liu, Xiaoyu, Chen, Jie, Zhou, Yabo, Lv, Jiadi, Zhou, Nannan, Ma, Jingwei, Tang, Ke, Huang, Bo

Issue&Volume: 2024-09-11

Abstract: Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.

DOI: 10.1038/s41556-024-01503-x

Source: https://www.nature.com/articles/s41556-024-01503-x