Insulin-like growth factor binding protein-3 mediates hyperosmolar stress-induced mitophagy through the mechanistic target of rapamycin.
Insulin-like growth factor binding protein-3 mediates hyperosmolar stress-induced mitophagy through the mechanistic target of rapamycin.
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DOI：
10.1016/j.jbc.2023.105239
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发表时间：
2023-11
影响因子：
4.8
通讯作者：
Robertson, Danielle M.
中科院分区：
文献类型：
--
作者：
Sambhariya, Whitney Stuard;Trautmann, Ian J.;Robertson, Danielle M.
眼表高渗触发干眼病（DED）的炎症和病理损伤。除了降低生活质量外，DED还会导致视力丧失，严重时还会导致失明。线粒体功能障碍是高渗应激的结果。我们之前报道了胰岛素样生长因子结合蛋白-3 （IGFBP-3）在调节粘膜表面上皮细胞线粒体超微结构和代谢中的作用；然而，这似乎是特定于上下文的。由于在体外和DED动物模型中发现IGFBP-3表达在高渗应激下降低，我们接下来试图确定高渗应激介导的IGFBP-3表达降低是否会改变线粒体自噬，这是线粒体质量控制的关键机制。本研究表明，高渗透压胁迫通过对BNIP3L/NIX和pink1介导途径的差异调控诱导有丝分裂。在角膜上皮细胞中，这与p62无关。外源IGFBP-3的加入消除了线粒体自噬的增加。这是通过调控mTOR发生的，突出了新的IGFBP-3-mTOR信号通路的存在。总之，这些发现支持IGFBP-3在DED中介导线粒体质量控制的新作用，并对受高渗透压应激和其他线粒体疾病影响的上皮组织具有广泛的意义。
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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影响因子：
2.6
作者：
Marinković M;Novak I
通讯作者：
Novak I
影响因子：
5.6
作者：
通讯作者：
--
影响因子：
5.6
作者：
Png, Evelyn;Samivelu, G. K.;Tong, Louis
通讯作者：
Tong, Louis
影响因子：
2.8
作者：
Luo, Lihui;Li, De-Quan;Pflugfelder, Stephen C.
通讯作者：
Pflugfelder, Stephen C.
影响因子：
4.4
作者：
Gipson, IK;Spurr-Michaud, S;Russo, CL
通讯作者：
Russo, CL