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Scientists Reveal the Role of Cross-talk Between Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in the Genotoxic Response of Fresh and Aged Zinc Oxide Nanoparticles in Mammalian Cells
A Chinese research team led by Prof. XU An in Institute of Technical Biology & Agriculture Engineering, Hefei Institutes of Physical Science recently revealed that mitochondrial dysfunction and endoplasmic reticulum (ER) stress made different contribution to the genotoxicity of fresh and aged zinc oxide nanoparticles (ZnO NPs) in mammalian cells.

ZnO NPs are being produced abundantly and applied increasingly in various fields. The special physicochemical characteristics of ZnO NPs makes them incline to undergo physicochemical transformation over time (aging), which modify their bioavailability and toxicity. However, the subcellular targets and the underlying molecular mechanisms involved in the genotoxicity induced by ZnO NPs during aging process are still unknown.

In XU’s
study, they investigated the role of mitochondrial dysfunction and ER stress interaction in the genotoxicity induced by fresh and aged ZnO NPs by using human-hamster hybrid (AL) cells and mitochondria DNA-depleted (rho0) AL cells together with ROS scavengers and an ER stress inhibitor.

They found that the acute cytotoxicity of fresh ZnO NPs was largely regulated by mitochondria-dependent apoptosis, which the level of cleaved Caspase-3 and mitochondria damage were significantly higher than that of aged ZnO NPs. In contrast, aged ZnO NPs induced more reactive oxygen species (ROS) production and ER stress marker protein (BIP/GRP78) expression and their genotoxicity could be dramatically suppressed by either ROS scavengers (dimethyl sulfoxide, catalase, and sodium azide) or ER stress inhibitor (4-phenylbutyrate). Using rho0 AL cells, we further found that ER stress induced by aged ZnO NPs was triggered by ROS generated from mitochondria, which eventually mediated the genotoxicity of aged NPs.

Their work identifies a new subcellular mechanism involving cross-talk between mitochondria and the ER in the induction of fresh and aged ZnO NPs-induced genotoxicity, which provides novel insights into risk assessments of ZnO NPs in the environment, and basis for the safe application of ZnO NPs and prevention of related diseases.

This work was supported by Strategic Leading Science & Technology Program (B), Major National Scientific Research Projects, National Natural Science Foundation of China grants, Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology; CASHIPS Director’s Fund, China Postdoctoral Science Foundation, and Anhui Province Postdoctoral Science Foundation.

Schematic illustration of mechanism(Image by WANG Juan)