The Effects Of Nickel Chloride On Mitochondrial Damage And Mitophagy In Liver Of Mice

Nickel is widely used in industry and food industry for its good metal properties.With the increasing application of nickel,its accompanying environmental pollution problem is also increasingly prominent.Nickel is an important toxic and carcinogenic substance in the environment,which can cause liver,kidney,lung and brain toxicity in animals.There have been a series of reports on the toxicity of nickel to liver,but few reports on the effect of liver mitochondria.In this study,the mouse model of nickel chloride exposure was established to observe the changes of the level of oxidative stress,mitochondrial function,mitochondria biological,mitochondria fission and fusion and mitophagy in liver,and to explore mitochondrial damage and mitophagy in the role and mechanism of nickel-induced liver damage,further to provide theoretical basis for the prevention and control of nickel chloride poisoning.In this study,128 7-week-old ICR male mice were randomly divided into 4 groups,namely control group（0 mg/kg NiCl₂）,7.5 mg/kg NiCl₂ group,15 mg/kg NiCl₂ group and30 mg/kg NiCl₂ group,and administered by gavage for 28 consecutive days.On day 14 and28 of the experiment,histopathological,biochemical,ELISA,flow cytometry,Western blotting,and q RT-PCR were used to detect the histopathological changes,mitochondrial damage,and mitophagy levels.The results are as follows:（1）NiCl₂ induced pathological changes in liver: Nickel content in liver of NiCl₂ treated groups increased in a dose-dependent manner,and liver index of 30 mg/kg NiCl₂ group increased significantly on day 28 of the experiment.NiCl₂ injured the liver structure of mice,involving hepatic cord arrangement disorder,hepatic cell swelling,granular and vacuolar degeneration in hepatocyte.Meanwhile,the liver function was significantly decreased in NiCl₂ treated groups,including the contents of ALT and AST in serum were significantly increased（P < 0.05）.（2）NiCl₂ induced oxidative stress in liver: On day 14 and 28 of the experiment,MDA contents in 15 and 30 mg/kg NiCl₂ groups were significantly increased,while GSH and T-AOC contents in 30 mg/kg NiCl₂ group were significantly decreased（P < 0.05）.（3）NiCl₂ induced mitochondrial dysfunction in liver: On day 14 and 28 of the experiment, the percentages of mitochondrial membrane potential and mt-ROS content in 30 mg/kg NiCl₂ group was significantly increased,while the content of ATP and the activities of mitochondrial complex Ⅰ,II,III and IV in 30 mg/kg NiCl₂ group were significantly decreased（P < 0.05）.（4）NiCl₂ inhibited mitochondrial biogenesis in liver: On day 14 and 28 of the experiment,the m RNA and protein expression levels of PGC-1α,Nrf1 and TFAM in 30 mg/kg NiCl₂ group were significantly decreased（P < 0.05）.（5）NiCl₂ interfered mitochondrial fusion and fission in liver: On day 14 and 28,the protein expression levels of Drp1 and Fis1 in 30 mg/kg NiCl₂ group were significantly increased,and the protein expression levels of Mfn1 and Mfn2 in 30 mg/kg NiCl₂ groups were significantly decreased（P < 0.05）.The m RNA expression levels of Drp1 and Fis1 in liver of 30 mg/kg NiCl₂ group were significantly increased（P < 0.05）,while the m RNA expression levels of Mfn1 and Mfn2 were significantly decreased（P < 0.05）.（6）NiCl₂ induced mitophagy in the liver: On day 14 and 28,the protein expression levels of Pink1,Parkin and p62 in the cytoplasm were significantly decreased in 30 mg/kg NiCl₂ group,while the protein expression levels of LC3II/I in 15 and 30 mg/kg NiCl₂ group were significantly increased（P < 0.05）.The protein expression levels of Pink1,Parkin,p62 and LC3II/I in mitochondria in 15 and 30 mg/kg NiCl₂ groups were significantly increased（P <0.05）.On the 14 th and 28 th day of the experiment,the m RNA and protein expression levels of BNIP3 and FUNDC1 in 30 mg/kg NiCl₂ group were significantly increased.In conclusion,NiCl₂ damaged the structural and function of liver in mice.The main mechanisms of NiCl₂-induced liver injury included oxidative damage,mitochondrial biogenesis disorder,the decrease of mitochondrial function and fusion,and the increase of mitochondrial fission and mitophagy.