한빛사 논문
Gee Euhn Choi1, Hyun Jik Lee2,3, Chang Woo Chae1, Ji Hyeon Cho1, Young Hyun Jung1, Jun Sung Kim1, Seo Yihl Kim1, Jae Ryong Lim1 & Ho Jae Han1,*
1Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul 08826, South Korea. 2Laboratory of Veterinary Physiology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Korea. 3Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, Chungbuk 28644, South Korea
*Corresponding author
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.
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