Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Toxicol Lett. 2018 Jul;291:92-100. doi: 10.1016/j.toxlet.2018.04.012. Epub 2018 Apr 13.
Lead (Pb), a widely distributed environmental pollutant, is known to induce mitochondrial damage as well as autophagy in vitro and in vivo. In this study, we found that Pb could trigger mitophagy in both HEK293 cells and the kidney cortex of male Kunming mice. However, whether ataxia telangiectasis mutated (ATM) which is reported to be linked with PTEN-induced putative kinase 1 (PINK1)/Parkin pathway (a well-characterized mitophagic pathway) participates in the regulation of Pb-induced mitophagy and its exact role remains enigmatic. Our results indicated that Pb activated ATM in vitro and in vivo, and further in vitro studies showed that ATM could co-localize with PINK1 and Parkin in cytosol and interact with PINK1. Knockdown of ATM by siRNA blocked Pb-induced mitophagy even under the circumstance of enhanced accumulation of PINK1 and mitochondrial Parkin. Intriguingly, elevation instead of reduction in phosphorylation level of PINK1 and Parkin was observed in response to ATM knockdown and Pb did not contribute to the further increase of their phosphorylation level, implying that ATM indirectly regulated PINK1/Parkin pathway. These findings reveal a novel mechanism for Pb toxicity and suggest the regulatory importance of ATM in PINK1/Parkin-mediated mitophagy.
铅（Pb）是一种广泛分布的环境污染物，已知其在体外和体内均可诱导线粒体损伤和自噬。在这项研究中，我们发现 Pb 可在 HEK293 细胞和雄性昆明小鼠肾脏皮质中引发线粒体自噬。然而，与 PTEN 诱导的假定激酶 1（PINK1）/Parkin 途径（一种公认的线粒体自噬途径）相关的共济失调毛细血管扩张突变（ATM）是否参与调节 Pb 诱导的线粒体自噬及其确切作用仍不清楚。我们的结果表明，Pb 在体外和体内激活了 ATM，进一步的体外研究表明，ATM 可以在细胞质中与 PINK1 和 Parkin 共定位，并与 PINK1 相互作用。用 siRNA 敲低 ATM 可阻断 Pb 诱导的线粒体自噬，即使在 PINK1 和线粒体 Parkin 积累增强的情况下也是如此。有趣的是，敲低 ATM 后观察到 PINK1 和 Parkin 的磷酸化水平升高而非降低，而 Pb 并未导致其磷酸化水平进一步升高，这表明 ATM 间接调节了 PINK1/Parkin 途径。这些发现揭示了 Pb 毒性的一种新机制，并表明 ATM 在 PINK1/Parkin 介导的线粒体自噬中的调节重要性。
