Involvement of PINK1/parkin-mediated mitophagy in ZnO nanoparticle-induced toxicity in BV-2 cells

Abstract

With the increasing application of zinc oxide nanoparticles (ZnO NPs) in biological materials, the neurotoxicity caused by these particles has raised serious concerns. However, the underlying molecular mechanisms of the toxic effect of ZnO NPs on brain cells remain unclear. Mitochondrial damage has been reported to be a factor in the toxicity of ZnO NPs. PINK1/parkin-mediated mitophagy is a newly emerging additional function of autophagy that selectively degrades impaired mitochondria. Here, a PINK1 gene knockdown BV-2 cell model was established to determine whether PINK1/parkin-mediated mitophagy was involved in ZnO NP-induced toxicity in BV-2 cells. The expression of total parkin, mito-parkin, cyto-parkin, and PINK1 both in wild type and PINK1 −/− BV-2 cells was evaluated using Western blot analysis after the cells were exposed to 10 μg/mL of 50 nm ZnO NPs for 2, 4, 8, 12, and 24 h. The findings suggested that the downregulation of PINK1 resulted in a significant reduction in the survival rate after ZnO NP exposure compared with that of control cells. ZnO NPs were found to induce the transportation of parkin from the cytoplasm to the mitochondria, implying the involvement of mitophagy in ZnO NP-induced toxicity. The deletion of the PINK1 gene inhibited the recruitment of parkin to the mitochondria, causing failure of the cell to trigger mitophagy. The present study demonstrated that apart from autophagy, PINK1/parkin-mediated mitophagy plays a protective role in ZnO NP-induced cytotoxicity.

Neurotoxic effect of active ingredients in sunscreen products, a contemporary review

“…Cytotoxicity observed in the glioma cells was related to increased ROS generation, and N -acetyl- l -cysteine (NAC) treatment decreased the cytotoxic effect of the ZnO NPs in these cells [123] . ZnO NP-induced cytotoxicity was also observed in microglia (BV-2 cells) exposed to 10 μg/ml ZnO NPs for 2–24 h [125] . ZnO NPs induced parkin protein translocation from the cytoplasm to the mitochondria, implying the involvement of mitophagy in ZnO NPs-induced toxicity [125] .…”

“…ZnO NP-induced cytotoxicity was also observed in microglia (BV-2 cells) exposed to 10 μg/ml ZnO NPs for 2–24 h [125] . ZnO NPs induced parkin protein translocation from the cytoplasm to the mitochondria, implying the involvement of mitophagy in ZnO NPs-induced toxicity [125] .…”

“… [124] BV-2 mice microglia cell line 2–24 h 10 μg/ml Increased cytotoxicity; activated PINK1/parkin-mediated mitophagy. [125] Abbreviations : 5-HT: 5-hydroxytriptamine; Akt: protein kinase B; cAMP: cyclic adenosine monophosphate; CAT: catalase; CREB: cAMP response element binding protein; CRP: c-reactive protein; DA: dopamine; ERK: extracellular signal-related kinase; GSH: glutathione; GPx: glutathione peroxidase; GST: glutathione-S-transferase; H2AX: H2A histone family member X; IL-1β: interleukin-1β; IL-6: interleukin-6; JNK: c-Jun N-terminal kinase; LDH: lactate dehydrogenase; LOX: lipoxygenase; MDA: malondialdehyde; MMP: mitochondrial membrane potential; NE: norepinephrine; NPs: nanoparticles; p38 MAPK: p38 mitogen-activated protein kinase; PINK1: PTEN-induced putative kinase 1; PI3 K: phosphoinositide 3-kinase; ROS: reactive oxygen species; SOD: superoxide dismutase; TNF-α: tumor necrosis factor α; Zn: zinc; ZnO: zinc oxide. …”

Neuroinflammation is induced by tongue-instilled ZnO nanoparticles via the Ca2+-dependent NF-κB and MAPK pathways

“…ROS might be a key mediator of inflammatory conditions, potentially stimulated by increased intracellular Ca 2+ , and further activate the NF-κB, ERK and p38 pathways, resulting in inflammation. Our previous studies also found that ZnO NPs induced oxidative damage in the brain after tongue instillation for 30 days, and ROS levels were enhanced in BV2 cells after 10 μg/mL NPs treatment [ 15 , 81 ]. Furthermore, enhanced Ca 2+ levels can lead to the activation of protein kinase C (PKC), which is involved in the activation of NF-κB and ERK [ 82 – 84 ].…”

Paraquat Exposure Induces Pulmonary Cell Mitophagy by Enhancing the PINK1/Parkin Signaling

“…Mitophagy is a selective autophagy process and is crucial for the maintenance of mitochondrial function in many types of cells [10]. It is well known that PQ can induce oxidative stress and produce ROS, leading to depletion of antioxidants and development of mitophagy and fibrosis [3,11,12]. Actually, previous studies have shown that PQ exposure decreased the MMP and increased PINK1 and Parkin expression, leading to mitophagy and apoptosis in A549 cells [13].…”