Qi Yongmei, Qiu Qian, Gu Xueyan, Tian Yihong, Zhang Yingmei
Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Qibo Medical School, Longdong University, Qingyang 745000, China.
Sci Rep. 2016 Apr 19;6:24700. doi: 10.1038/srep24700.
The ATM (ataxia telangiectasia mutated) protein has recently been proposed to play critical roles in the response to mitochondrial dysfunction by initiating mitophagy. Here, we have used ATM-proficient GM00637 cells and ATM-deficient GM05849 cells to investigate the mitophagic effect of spermidine and to elucidate the role of ATM in spermdine-induced mitophagy. Our results indicate that spermidine induces mitophagy by eliciting mitochondrial depolarization, which triggers the formation of mitophagosomes and mitolysosomes, thereby promoting the accumulation of PINK1 and translocation of Parkin to damaged mitochondria, finally leading to the decreased mitochondrial mass in GM00637 cells. However, in GM05849 cells or GM00637 cells pretreated with the ATM kinase inhibitor KU55933, the expression of full-length PINK1 and the translocation of Parkin are blocked, and the colocalization of Parkin with either LC3 or PINK1 is disrupted. These results suggest that ATM drives the initiation of the mitophagic cascade. Our study demonstrates that spermidine induces mitophagy through ATM-dependent activation of the PINK1/Parkin pathway. These findings underscore the importance of a mitophagy regulatory network of ATM and PINK1/Parkin and elucidate a novel mechanism by which ATM influences spermidine-induced mitophagy.
最近有人提出，共济失调毛细血管扩张症突变（ATM）蛋白通过启动线粒体自噬，在应对线粒体功能障碍方面发挥关键作用。在此，我们使用ATM功能正常的GM00637细胞和ATM缺陷的GM05849细胞，研究亚精胺的线粒体自噬作用，并阐明ATM在亚精胺诱导的线粒体自噬中的作用。我们的结果表明，亚精胺通过引发线粒体去极化来诱导线粒体自噬，这会触发线粒体自噬体和线粒体溶酶体的形成，从而促进PINK1的积累以及Parkin向受损线粒体的转位，最终导致GM00637细胞中线粒体质量的下降。然而，在用ATM激酶抑制剂KU55933预处理的GM０5849细胞或GM00637细胞中，全长PINK1的表达和Parkin的转位被阻断，并且Parkin与LC3或PINK1的共定位被破坏。这些结果表明，ATM驱动线粒体自噬级联反应的启动。我们的研究表明，亚精胺通过依赖ATM激活PINK1/Parkin途径来诱导线粒体自噬。这些发现强调了ATM和PINK1/Parkin的线粒体自噬调节网络的重要性，并阐明了ATM影响亚精胺诱导的线粒体自噬的新机制。
