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BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects

Author

Listed:
  • Gee Euhn Choi

    (Seoul National University)

  • Hyun Jik Lee

    (Chungbuk National University
    Chungbuk National University)

  • Chang Woo Chae

    (Seoul National University)

  • Ji Hyeon Cho

    (Seoul National University)

  • Young Hyun Jung

    (Seoul National University)

  • Jun Sung Kim

    (Seoul National University)

  • Seo Yihl Kim

    (Seoul National University)

  • Jae Ryong Lim

    (Seoul National University)

  • Ho Jae Han

    (Seoul National University)

Abstract

Stress-induced glucocorticoids disturb mitochondrial bioenergetics and dynamics; however, instead of being removed via mitophagy, the damaged mitochondria accumulate. Therefore, we investigate the role of glucocorticoids in mitophagy inhibition and subsequent synaptic defects in hippocampal neurons, SH-SY5Y cells, and ICR mice. First, we observe that glucocorticoids decrease both synaptic density and vesicle recycling due to suppressed mitophagy. Screening data reveal that glucocorticoids downregulate BNIP3-like (BNIP3L)/NIX, resulting in the reduced mitochondrial respiration function and synaptic density. Notably, we find that glucocorticoids direct the glucocorticoid receptor to bind directly to the PGC1α promoter, downregulating its expression and nuclear translocation. PGC1α downregulation selectively decreases NIX-dependent mitophagy. Consistent with these results, NIX enhancer pre-treatment of a corticosterone-exposed mouse elevates mitophagy and synaptic density in hippocampus, improving the outcome of a spatial memory task. In conclusion, glucocorticoids inhibit mitophagy via downregulating NIX and that NIX activation represents a potential target for restoring synapse function.

Suggested Citation

  • Gee Euhn Choi & Hyun Jik Lee & Chang Woo Chae & Ji Hyeon Cho & Young Hyun Jung & Jun Sung Kim & Seo Yihl Kim & Jae Ryong Lim & Ho Jae Han, 2021. "BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20679-y
    DOI: 10.1038/s41467-020-20679-y
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