Department 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.
Laboratory of Veterinary Physiology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 28644, Korea.
Nat Commun. 2021 Jan 20;12(1):487. doi: 10.1038/s41467-020-20679-y.
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.
应激诱导的糖皮质激素扰乱线粒体生物能和动力学；然而，受损的线粒体并没有通过线粒体自噬被清除，而是积累起来。因此，我们研究了糖皮质激素在海马神经元、SH-SY5Y 细胞和 ICR 小鼠中线粒体自噬抑制和随后的突触缺陷中的作用。首先，我们观察到糖皮质激素由于抑制了线粒体自噬而降低了突触密度和囊泡回收。筛选数据显示，糖皮质激素下调 BNIP3 样（BNIP3L）/NIX，导致线粒体呼吸功能和突触密度降低。值得注意的是，我们发现糖皮质激素指导糖皮质激素受体直接结合 PGC1α 启动子，下调其表达和核易位。PGC1α 的下调选择性地减少了依赖 NIX 的线粒体自噬。与这些结果一致的是，给予皮质酮暴露的小鼠 NIX 增强剂预处理可提高海马体中的线粒体自噬和突触密度，改善空间记忆任务的结果。总之，糖皮质激素通过下调 NIX 抑制线粒体自噬，而 NIX 的激活代表了恢复突触功能的潜在靶点。
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