Silica nanoparticles perturbed mitochondrial dynamics and induced myocardial apoptosis via PKA-DRP1-mitochondrial fission signaling

Silica nanoparticles (SiNPs) are among the most abundantly produced nanosized particles in the global market, and their potential toxicity has aroused a great concern. Increasing epidemiological investigations and experimental evidence revealed the threaten of SiNPs exposure to cardiovascular system. The myocardial toxicity caused by SiNPs was gradually demonstrated, nevertheless, the underlying mechanisms remain unclear. In view of mitochondria serving as the centrality in the prominent of cardiovascular disease, we investigated the role of mitochondria and related mechanisms in SiNPs-induced adverse effects on cardiomyocytes. As a result, SiNPs were found in cytoplasm, accompanied with morphological alterations in mitochondria, such as cristae fracture or disappearance, vacuolation. The induction of mitochondrial dysfunction by SiNPs was confirmed, as indicated by the excessive reactive oxygen species (ROS) formation, and blockage of cellular respiratory and ATP production. Concomitantly, SiNPs activated mitochondria-mediated apoptotic signaling in view of the up-regulated BAX, increased Caspase-9 cleavage and declined Bcl-2, ultimately resulting in myocardial apoptosis. It was noteworthy that SiNPs disturbed mitochondrial dynamics toward fission phenotype, which was supported by the dysregulated fission/fusion regulators. Especially, DRP1 and its phosphorylated level at s616 (p-DRP1s616) were up-regulated, whilst its phosphorylated level at s637 (p-DRP1s637) and PKA phosphorylation were down-regulated in SiNPs-treated cardiomyocytes in a dose-dependent manner. More importantly, the mechanistic investigations revealed PKA-DRP1-mediated mitochondrial fission was responsible for SiNPs-induced cardiomyocyte apoptosis through the mitochondria-mediated apoptotic way. This study firstly demonstrated the disturbance of mitochondrial dynamics played a crucial role in cardiomyocyte apoptosis caused by SiNPs, attributing to PKA-DRP1-mitochondrial fission signaling.