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

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

  • Nat Cell Biol. 2024 Sep 11. doi: 10.1038/s41556-024-01503-x.
Huafeng Zhang # 1 2 3,  Jincheng Liu # 4,  Wu Yuan 5,  Qian Zhang 1 2,  Xiao Luo 1 2,  Yonggang Li 6,  Yue'e Peng 7,  Jingyu Feng 8,  Xiaoyu Liu 1 2,  Jie Chen 5,  Yabo Zhou 5,  Jiadi Lv 5,  Nannan Zhou 5,  Jingwei Ma 9,  Ke Tang 3 8,  Bo Huang 10 11
Affiliations

Affiliations

  • 1 Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, China.
  • 4 College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 6 Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China.
  • 7 State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, China.
  • 8 Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 9 Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 10 Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. tjhuangbo@hotmail.com.
  • 11 Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. tjhuangbo@hotmail.com.
  • # Contributed equally.
PMID: 39261719 DOI: 10.1038/s41556-024-01503-x
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.

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