[Southeast University News Network, Nov. 1] (Correspondent: Chai Renjie) On Oct. 31, Prof. Chai Renjie from the School of Life Science and Technology of Southeast University and Prof. Jin Jin from Zhejiang University jointly published a research paper titled “Stress-induced metabolic disorder in peripheral CD4+ T cells leads to anxiety-like behavior” in Cell magazine. This paper indicates the link between CD4+ T cell purine anabolic dysfunction and chronic stress-induced mental illness. This is the first time that Southeast University has published the research achievement in the name of the corresponding unit in Cell, the top journal of biology.
The mitochondria can provide energy for the life activities of cells, and the changes in their mitochondrial morphology are involved in the regulation of cellular metabolism, which is essential for the normal development and maintenance of cells. Miga2 is a mitochondrial outer membrane protein. Knocking out Miga2 can result in severe damage to the mitochondrial raft structure, and therefore, the mitochondria may lose its normal tubular or reticular morphology but form a fragmented morphology. In the electrophysiological audiology test, Prof. Chai Renjie’s team found that after specifically knocking out MIGA2 in the mice’s T cells, the mice showed hearing impairment, and the auditory brainstem-evoked reaction (ABR) as stimulated by ambient sounds of various frequency is lower than that of normal mice. In order to further understand how the mitochondrial morphology in immune cells affects the animal’s physiological reaction, Prof. Chai Renjie’s team worked with Prof. Jin Jin’s team from Zhejiang University. They adopted various animal behavioral experiments as the evaluation criteria. It was found that the mice lacking CD4+ T cells in the body can avoid the chronic stress-induced mental illness under external pressure. The experimental data showed that under chronic stress, the content of leukotriene b4 in mice increased; as a result, a large number of non-inflammatory CD4+ T cell mitochondria including Naive T cells were fragmented. The corresponding metabolomics and transcriptome analysis indicated that the mitochondrial fragmentation in CD4+ T cells may lead to the accumulation of the transcription factor IRF1. The combination of IRF1 with Ada, Xdh and Pnp2 promoter regions enables more glucose to be metabolized through the pentose-phosphate pathway, promoting purine synthesis from scratch. In the chronic stress anxiety model, the serum xanthine in mice increased significantly. The clinical evidences collected by Prof. Chai Renjie’s team from Nanjing Gulou Hospital also showed that the patients with anxiety disorders had elevated serum xanthine when compared with the healthy controls. The brain amygdala plays a key role in the production of fear and anxiety. Excessive purine produced by T cells (including hypoxanthine and xanthine) enters the brain through the blood circulation, and combines with adenosine receptor A1 on the oligodendrocytes in the amygdala on the left side of the brain. Such combination then causes the oligodendrocyte activation and proliferation. The over-activation of neurons in the left amygdaloid nucleus area leads to anxiety symptoms. At the same time, an adeno-associated virus is injected into the left amygdala of the mice by using a brain localization injection device to specifically knock out the receptor A1 in oligodendrocytes. As a result, the symptoms of anxiety mice were significantly improved after A1 has been knocked out, which further verified the above conclusion.
This study result has determined how the chronic stress affects the mitochondrial morphology in CD4+ T cells and elucidated the specific role of peripheral T cells in anxiety-like behaviors induced by chronic stress. Most drugs for clinical treatment of mental illness directly target the central nervous system, often with many side effects. Deepening the understanding of the relationship among neurodevelopment, mental illness and immune physiology is of great significance for understanding the pathogenesis of depression and anxiety and developing new therapeutic drugs.
The project was funded by the National Key Research and Development Program of the Ministry of Science and Technology, the Outstanding Youth Fund of the National Natural Science Foundation of China, the Class-A Strategic Pilot Science and Technology Programtitled “Organ Regeneration and Manufacturing” as initiated by the Chinese Academy of Sciences, and the National Natural Science Foundation of China, etc..
Submitted by: the School of Life Science and Technology
(Editor-in-charge: Wu Chan, reviewed by: Li Xiaonan)