Key Role of Microtubule and Its Acetylation in a Zinc Oxide Nanoparticle–Mediated Lysosome–Autophagy System

Abstract

Autophagy is a biological process that has attracted considerable attention as a target for novel therapeutics. Recently, nanomaterials (NMs) have been reported to modulate autophagy, which makes them potential agents for the treatment of autophagy‐related diseases. In this study, zinc oxide nanoparticles (ZNPs) are utilized to evaluate NM‐induced autophagy and debate the mechanisms involved. It is found that ZNPs undergo pH‐dependent ion shedding and that intracellular zinc ions (Zn2+) play a crucial role in autophagy. Autophagy is activated with ZNPs treatment, which is inhibited after Zn2+ sequestration via ethylenediamine tetra‐acetic acid. Lysosome‐based autophagic degradation is halted after ZNPs treatment for more than 3 h and is accompanied by blockage of lysophagy, which renews impaired lysosomes. Furthermore, the microtubule (MT) system participates in ZNP‐induced lysosome–autophagy system changes, especially in the fusion between autophagosomes and lysosomes. MT acetylation is helpful for protecting from ZNP‐induced MT disruption, and it promotes the autophagic degradation process. In conclusion, this study provides valuable information on NM‐induced lysosome–autophagy system changes, particularly with respect to the role of lysophagy and the MT system, which point to some attractive targets for the design of engineered nanoparticles.

Selective Autophagy Pathway of Nanoparticles and Nanodrugs: Drug Delivery and Pathophysiological Effects

“…[102][103][104][105][106][107][108][109][110][111][112] Metal nanoparticles including alpha-aluminum oxide, [119] copper, [120,121] cobalt chromium-molybdenum, [122] cuprous oxide, [124] iron oxide, [125,126] cobalt and chromium, [123] silica, [127][128][129][130]133] silver, [131,132] zinc oxide, [134,135] upconversion, [136,137,147] and titanium dioxide [90,138] are intracellularly trafficked through endocytosis or another uptake pathway and processed through the autophagy pathway. [90,[119][120][121][122][123][124][125][126][127][128][129][130][131][132]…”

“…Examples of organic nanocarriers are polymeric nanoparticles, [102,105,106,[159][160][161] nanoliposomes, [162] and nanogels [111] and those of inorganic nanocarriers are carbon [163,164] and metal nanoparticles. [129,147,165] Drugs such as atazanavir, [160,161] bafilomycin A1, [147] brefeldin A, [166] ceramide, [162] cisplatin, [164,167] docetaxel, [102,105,106] doxorubicin, [111] fumagillin, [163] paclitaxel, [129,159,168] small molecule inhibitor 9 (SMI#9), [165] temozolomide, [159] and vinblastine [162] can be loaded onto various nanocarriers. These nanodrugs are intracellularly trafficked and processed through the autophagy pathway in various cell types, as shown in Table 2.…”

“…[31,32,95] Studies have reported that various nanoparticles and nanodrugs cause lysosomal dysfunction including dendrimers, [214] gold, [202] iron oxide, [125] silica, [215] silver, [216] polymeric materials, [213,217] titanium oxide, [218,219] and zinc oxide. [168] Lysophagy is another type of selective autophagy pathway by the degradation of damaged lysosomes. [58,220] Studies have revealed that the silica nanoparticle induced lysophagy, which caused the rupture of lysosomes through the disruption of the lysosomal membrane.…”

Autophagy Modulators: Mechanistic Aspects and Drug Delivery Systems

“…Upconversion NPs encapsulating chlorin e6 effectively enhance the generation of ROS and subsequently, stimulate autophagy through PI3K/Akt/mTOR signaling pathway, resulting in down-regulation of pro-inflammatory factors (IL-12, TNF-α and iNOS) production [12]. Taking everything into account, NPs are able to regulate autophagy and this potential can be promisingly used in biomedical applications [334]. However, these nanoparticles could also trigger other organ toxicity tightly related with autophagy.…”

Chemosensitivity enhanced by autophagy inhibition based on a polycationic nano-drug carrier

“…Finally, autolysosomes are disassembled, providing nutrition and energy for cells in response to many severe cellular conditions. 4,5 Recent studies have shown that autophagy dysfunction is associated with tumors, 6 neurodegenerative diseases, 7 cardiovascular diseases 8 and infections. 9 Compared to other pathophysiology, the role of autophagy in cancer is more complicated because autophagy plays a "doubleedged sword" role in various types of cancer, 10,11 mediating carcinogenesis or anticancer effects.…”