Insulin-like growth factor binding protein-3 mediates hyperosmolar stress-induced mitophagy through the mechanistic target of rapamycin.

The Journal of Biological Chemistry Pub Date : 2023-11-01 Epub Date: 2023-09-09 DOI:10.1016/j.jbc.2023.105239
Whitney Stuard Sambhariya, Ian J Trautmann, Danielle M Robertson
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Abstract

Hyperosmolarity of the ocular surface triggers inflammation and pathological damage in dry eye disease (DED). In addition to a reduction in quality of life, DED causes vision loss and when severe, blindness. Mitochondrial dysfunction occurs as a consequence of hyperosmolar stress. We have previously reported on a role for the insulin-like growth factor binding protein-3 (IGFBP-3) in the regulation of mitochondrial ultrastructure and metabolism in mucosal surface epithelial cells; however, this appears to be context-specific. Due to the finding that IGFBP-3 expression is decreased in response to hyperosmolar stress in vitro and in an animal model of DED, we next sought to determine whether the hyperosmolar stress-mediated decrease in IGFBP-3 alters mitophagy, a key mitochondrial quality control mechanism. Here we show that hyperosmolar stress induces mitophagy through differential regulation of BNIP3L/NIX and PINK1-mediated pathways. In corneal epithelial cells, this was independent of p62. The addition of exogenous IGFBP-3 abrogated the increase in mitophagy. This occurred through regulation of mTOR, highlighting the existence of a new IGFBP-3-mTOR signaling pathway. Together, these findings support a novel role for IGFBP-3 in mediating mitochondrial quality control in DED and have broad implications for epithelial tissues subject to hyperosmolar stress and other mitochondrial diseases.

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胰岛素样生长因子结合蛋白-3通过雷帕霉素的机制靶点介导高渗应激诱导的线粒体自噬。
干眼病(DED)中,眼表面的高渗压会引发炎症和病理损伤。除了降低生活质量外,DED还会导致视力下降,严重时还会导致失明。线粒体功能障碍是高渗应激的结果。我们之前已经报道了胰岛素样生长因子结合蛋白-3(IGFBP-3)在粘膜表面上皮细胞线粒体超微结构和代谢调节中的作用;然而,这似乎是特定于上下文的。由于发现IGFBP-3的表达在体外和DED动物模型中对高渗应激的反应中降低,我们接下来试图确定高渗应激介导的IGFBP-3降低是否改变线粒体质量控制机制——线粒体自噬。在这里,我们发现高渗应激通过BNIP3L/NIX和PINK1介导的途径的差异调节诱导线粒体自噬。在角膜上皮细胞中,这与p62无关。外源性IGFBP-3的加入消除了线粒体自噬的增加。这是通过mTOR的调节发生的,突出了一种新的IGFBP-3-mTOR信号通路的存在。总之,这些发现支持了IGFBP-3在DED中介导线粒体质量控制的新作用,并对高渗应激和其他线粒体疾病的上皮组织具有广泛的意义。
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