This study investigated the mechanism of silver nanoparticle (AgNP) cytotoxicity from a mitochondrial perspective. The effect of AgNP on manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant enzyme, against oxidative stress has not been studied in detail. We demonstrated that AgNP decreased MnSOD mRNA level, protein expression, and activity in human Chang liver cells in a time-dependent manner. AgNP induced the production of mitochondrial reactive oxygen species (mtROS), particularly superoxide anion. AgNP was found to increase mitochondrial calcium level and disrupt mitochondrial function, leading to reduced ATP level, succinate dehydrogenase activity, and mitochondrial permeability. AgNP induced cytochrome c release from the mitochondria into the cytoplasm, attenuated the expression of the anti-apoptotic proteins phospho Bcl-2 and Mcl-1, and induced the expression of the pro-apoptotic proteins Bim and Bax. In addition, c-Jun N-terminal kinase (JNK) phosphorylation was significantly increased by AgNP. Treatment with elamipretide (a mitochondria-targeted antioxidant) and SP600125 (a JNK inhibitor) showed the involvement of MnSOD and JNK in these processes. These results indicated that AgNP damaged human Chang liver cells by destroying mitochondrial function through the accumulation of mtROS.
Keyphrases
- oxidative stress
- induced apoptosis
- diabetic rats
- signaling pathway
- cell death
- high glucose
- endothelial cells
- endoplasmic reticulum stress
- cell cycle arrest
- ischemia reperfusion injury
- dna damage
- reactive oxygen species
- gold nanoparticles
- pi k akt
- poor prognosis
- cell proliferation
- high resolution
- cell therapy
- induced pluripotent stem cells
- nitric oxide
- replacement therapy
- smoking cessation
- tyrosine kinase
- drug delivery
- bone marrow
- heat shock protein
- heat stress