ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts.
ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts.
复制标题
ATM 通过 PINK1 和 Parkin 调节人成纤维细胞介导亚精胺诱导的线粒体自噬
DOI：
10.1038/srep24700
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发表时间：
2016-04-19
影响因子：
4.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Qi Y;Qiu Q;Gu X;Tian Y;Zhang Y
ATM（共济失调毛细血管扩张突变）蛋白最近被提出通过启动线粒体自噬在线粒体功能障碍的反应中发挥关键作用。在此，我们使用精通ATM的GM00637细胞和缺乏ATM的GM05849细胞来研究亚精胺的线粒体自噬作用，并阐明ATM在精胺诱导的线粒体自噬中的作用。我们的研究结果表明，亚精胺通过诱导线粒体去极化来诱导线粒体自噬，线粒体去极化触发线粒体自噬体和线粒体溶酶体的形成，从而促进PINK1的积累和Parkin易位到受损线粒体，最终导致GM00637细胞线粒体质量下降。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的易位被阻断，Parkin与LC3或PINK1的共定位被破坏。这些结果表明，ATM驱动有丝分裂级联的启动。我们的研究表明，亚精胺通过atm依赖性激活PINK1/Parkin通路诱导有丝分裂。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。
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.