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BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α

Molecular Psychiatry (2023)Cite this article

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Abstract

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders.

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Fig. 1: NIX-mediated mitophagy is impaired by inflammation signaling.
Fig. 2: NIX-mediated mitophagy contributes to the stress-coping behaviors.
Fig. 3: Activation of NIX-mediated mitophagy alleviates TNF-α-induced mitochondrial dysfunction.
Fig. 4: Overexpression of NIX in the mPFC improves TNF-α-induced synaptic abnormalities.
Fig. 5: Ketamine and infliximab alleviate inflammation-induced behavioral abnormalities via activation of NIX-mediated mitophagy.
Fig. 6: NIX-mediated mitophagy negatively correlates with the severity of depressive symptoms and buffers CSDS-induced behavior abnormalities.

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Acknowledgements

This work was supported by the Foundation for National Key R&D Program of China (STI2030-Major Projects-2021ZD0202900/02/03 [to J-GC]), National Natural Science Foundation of China (Grant No. 82130110 [to J-GC] and Grant No. U21A20363 [to FW]), Innovative Research Groups of National Natural Science Foundation of China (Grant No. 81721005 [to J-GC and FW]), National Key R&D Program of China (Grant Nos. 2020YFA0803900 [to J-GC]), Program for Changjiang Scholars and Innovative Research Team in University (Grant No. IRT13016 [to J-GC.). We also thank Prof. Bin Hu and Dr. Zhi-Jun Yao, Lanzhou University, for kindly providing the blood samples of healthy control subjects and patients with MDD.

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  1. These authors contributed equally: Jia-Jing Lu, Peng-Fei Wu.

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jia-Jing Lu, Peng-Fei Wu, Jin-Gang He, Yu-Ke Li, Li-Hong Long, Xia-Ping Yao, Jia-Hao Yang, Hong-Sheng Chen, Zhuang-Li Hu, Fang Wang & Jian-Guo Chen

  2. The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, China

    Peng-Fei Wu, Li-Hong Long, Zhuang-Li Hu, Fang Wang & Jian-Guo Chen

  3. The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Peng-Fei Wu, Li-Hong Long, Zhuang-Li Hu, Fang Wang & Jian-Guo Chen

  4. The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China

    Peng-Fei Wu, Li-Hong Long, Zhuang-Li Hu, Fang Wang & Jian-Guo Chen

  5. Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Xiang-Nan Zhang & Zhong Chen

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Contributions

J-JL, FW, P-FW, and J-GC designed the study. J-JL and P-FW wrote the manuscript. J-JL performed most of the experiments and analyzed data. J-GH performed the single-cell microinjections. Y-KL conducted the behavioral tests and qPCR and bred transgenic mice. Y-PY performed the animal model of depression. J-HY assisted in identification of transgenic mice. X-NZ and ZC provided the Nix mutant mice and gave advice on the experiment. J-JL performed the western blotting. L-HL and Z-LH conducted the experiment. J-GC and FW supervised the project, revised the manuscript, and supported funding acquisition.

Corresponding authors

Correspondence to Fang Wang or Jian-Guo Chen.

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Lu, JJ., Wu, PF., He, JG. et al. BNIP3L/NIX-mediated mitophagy alleviates passive stress-coping behaviors induced by tumor necrosis factor-α. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02008-z

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