Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China.
Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China.
Sci Total Environ. 2023 Sep 1;889:164078. doi: 10.1016/j.scitotenv.2023.164078. Epub 2023 May 18.
Given their increasing industrial and biomedical applications, silver nanoparticles (AgNPs) have become widely present in the environment. However, to date, studies on their potential health risks have been far from sufficient, especially those regarding their neurotoxic effects. This study investigated the neurotoxic effects of AgNPs on neural PC-12 cells in the context of mitochondria, which play an important role in AgNP-induced cellular metabolism disturbance and even cell death. Our results show that the endocytosed AgNPs, and not extracellular Ag, appear to directly determine cell fate. Importantly, endocytosed AgNPs led to mitochondrial swelling and vacuolation without direct interaction. Although mitophagy, a selective autophagy process, was invoked to rescue damaged mitochondria, it failed to function in mitochondrial degradation and recycling. Discovery of the underlying mechanism showed that the endocytosed AgNPs could directly translocate into lysosomes and then cause lysosome perturbation, which is the main factor leading to mitophagy blockade and the subsequent accumulation of defective mitochondria. After lysosomal reacidification via cyclic adenosine monophosphate (cAMP), AgNP-induced dysfunctional autolysosome formation and disturbed mitochondrial homeostasis were reversed. In summary, this study reveals that lysosome-mitochondrion crosstalk is a main mechanism for AgNP-induced neurotoxic effects, offering an inspiring perspective on the neurotoxic effects of AgNPs.
鉴于其日益广泛的工业和生物医学应用，银纳米粒子（AgNPs）已经广泛存在于环境中。然而，迄今为止，关于其潜在健康风险的研究还远远不够，尤其是关于其神经毒性作用的研究。本研究探讨了 AgNPs 在涉及线粒体的情况下对神经 PC-12 细胞的神经毒性作用，线粒体在 AgNP 诱导的细胞代谢紊乱甚至细胞死亡中起着重要作用。我们的研究结果表明，内吞的 AgNPs 而不是细胞外的 Ag 似乎直接决定了细胞的命运。重要的是，内吞的 AgNPs 导致线粒体肿胀和空泡化，而没有直接相互作用。虽然自噬，一种选择性自噬过程，被调用以拯救受损的线粒体，但它在线粒体降解和回收中不起作用。对潜在机制的发现表明，内吞的 AgNPs 可以直接转位到溶酶体中，然后导致溶酶体扰动，这是导致自噬阻滞和随后积累缺陷线粒体的主要因素。通过环磷酸腺苷 (cAMP) 使溶酶体再酸化后，AgNP 诱导的功能失调的自噬体形成和紊乱的线粒体稳态得到逆转。总之，本研究揭示了溶酶体-线粒体串扰是 AgNP 诱导的神经毒性作用的主要机制，为 AgNPs 的神经毒性作用提供了一个有启发性的视角。
