VDAC1 oligomerization may enhance DDP‐induced hepatocyte apoptosis by exacerbating oxidative stress and mitochondrial DNA damage

Cisplatin (DDP)‐based chemotherapy is a preferred treatment for a broad spectrum of cancers, but the precise mechanisms of its hepatotoxicity are not yet clear. Recently, the role of voltage‐dependent anion channel protein 1 (VDAC1) in mitochondrial activity and cell apoptosis has attracted much attention. Our aim was to investigate the effects of mitochondrial outer membrane protein VDAC1 oligomerization in DDP‐induced hepatocyte apoptosis. L‐02 hepatocytes were divided into 4 groups: (a) control group, (b) 4,4'diisothiocyanate‐2,2'‐disulfonic acid (DIDS; 40 μm) group, (c) DDP (5 μm) group, and (d) DDP and DIDS combination group. Cell apoptosis was tested by Annexin V/FITC assay, protein expression of caspase‐3, γH2AX and NDUFB6 were observed by western blot assay, reactive oxygen species (ROS), and mitochondrial superoxide anion radical (O2 •−) were detected by DCFH‐DA and MitoSOX probe, and DNA damage was assessed by comet assay. Moreover, the activity of mitochondrial respiratory chain complex I was determined by the colorimetry method. Compared with the control group, apoptosis rate and activated cleaved‐caspase‐3 protein, ROS and O2 •− generation, DNA damage marker comet tail length, and γH2AX protein level increased in the DDP treatment group (P
This study found that DDP might convert VDAC1 monomers to VDAC1 oligomers, which promoted ROS and mtDNA fragments to be released from the mitochondria to the cytoplasm through VDAC1 channel, resulting in the expansion of mitochondrial oxidative stress and DNA damage. DIDS, an inhibitor of VDAC1 oligomerization, can alleviate DDP‐induced mitochondrial oxidative stress, DNA damage, and cell apoptosis in L‐02 hepatocytes.