Abstract
Mitochondria, as dynamic organelles, are precisely regulated by fusion and fission. The dynamic balance of fusion and fission controls mitochondrial morphology and their subcellular location and function. Exposure to titanium dioxide nanoparticles (TiO2NPs) may cause serious health problems. However, how TiO2NPs affect the mitochondrial dynamics remains unclear. In the present study, we investigated the changes of mitochondrial dynamics in the TiO2NPs-treated HT22 cells by confocal and stimulated emission depletion (STED) microscopy. The confocal images demonstrated obvious changes in the average length and density of the mitochondria after TiO2NPs treatment, while STED images further obtained the nanoscale submitochondrial structures of the mitochondria under TiO2NPs insult. The fluorescence intensity distributions suggested that mitochondria fragmented in the TiO2NPs-treated cells. TiO2NPs treatment caused mitochondrial dynamic imbalance due to the imbalanced expression of dynamin-related protein 1 (Drp1) and optic atrophy 1 (Opa1). Furthermore, we examined the levels of oxidative stress and mitochondrial membrane potential (MMP) and the generation of adenosine triphosphate (ATP), which revealed the damage of mitochondria under TiO2NPs exposure. Meanwhile, the significant changes of expressions of B-cell lymphoma 2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), cytochrome c (Cyt C), and caspase 9 demonstrated that TiO2NPs treatment activated the mitochondrial-related apoptosis pathway. These cellular events can be largely prevented via cell incubation with mitoTEMPO, a mitochondria-targeted superoxide scavenger. Our results confirm that TiO2NPs targeted the mitochondria, inducing mitochondrial dynamic imbalance and damage in HT22 cells. Our study provides an insightful understanding of the mechanisms underlying TiO2NPs cytotoxicity.
Highlights
Titanium dioxide nanoparticles (TiO2 NPs) have been increasingly used in various applications, such as food additives, sunscreen, cosmetics, toothpastes, and environmental decontamination [1,2,3,4,5]
According to dynamic light scattering (DLS) results, the Z-average of TiO2 NPs in the water was 270 73 ± 5 19 nm (Figure 1(c)), which meant that the hydrodynamic diameter of TiO2 NPs was much larger than the size revealed by transmission electron microscopy (TEM)
We examined oxidative stress (e.g., reactive oxygen species (ROS), MDA, and GSH), which indicated that the oxidative stress under TiO2 NPs exposure can be reversed by mitoTEMPO incubation (Supplementary Figure 4 A–C)
Summary
Titanium dioxide nanoparticles (TiO2 NPs) have been increasingly used in various applications, such as food additives, sunscreen, cosmetics, toothpastes, and environmental decontamination [1,2,3,4,5]. Studies estimated that annual TiO2 NPs production was between 5000 and 6400 tons [6, 7]. The expanding usage and the large amounts of TiO2 NPs being produced raise the risk of environmental exposure. TiO2 NPs may cause serious health problems. TiO2 NPs were reported to cause a clear epigenetic alteration in lung fibroblasts [8]. Even gestational exposure to TiO2 NPs impaired placentation [9].
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