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

Abstract

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 < 0.05). Activity of mitochondrial COXI decreased after DDP treatment (P < 0.05). DIDS, as a VDAC1 oligomerization inhibitor, antagonized DDP‐induced apoptosis by diminishing oxidative stress and DNA damage and protecting mitochondrial complex protein. These results show that VDAC1 oligomerization may play an important role in DDP‐induced hepatocyte apoptosis by increasing ROS and mtDNA leakage from VDAC1 pores, exacerbating oxidative stress and mtDNA damage.

Gut Microbiota Combined with Metabolomics Reveal the Mechanisms of Sika Deer Antler Protein on Cisplatin-Induced Hepatorenal Injury in Mice

“…The mechanisms of cisplatin-induced hepatorenal toxicity are related to mitochondrial dysfunction, oxidative stress, and inflammation [ 4 , 5 ]. Therefore, we evaluated the roles of SVPr1 and SVPr2 in improving mitochondrial dysfunction, oxidative stress, and inflammation in the liver and kidney induced by cisplatin.…”

“…Cisplatin induces an imbalance in the levels of oxidative stress and inflammatory response in the liver and kidney [ 4 , 5 ], whereas SVPr1 and SVPr2 administration could reduce cisplatin-induced adverse reactions by modulating the gut microbiota and metabolic pathways. To explore the possibility that the mitigation of cisplatin-induced injury by sika deer antler protein treatment may be initiated by pathogenic microbes and establish correlations between the presence of certain bacteria with the relief of hepatic and renal toxicity in mice, we performed microbiome analysis based on 16S rRNA sequencing.…”

“…Its antineoplastic property comes from its ability to crosslink with the purine bases on DNA and interfere with fundamental cellular processes such as replication and transcription in numerous cell types, ultimately leading to apoptosis [ 2 ]. Cisplatin also causes mitochondrial malfunction as a result of mitochondrial DNA (mtDNA) addition, causing reactive oxygen species (ROS) overproduction and boosting cytochrome c release, exacerbating oxidative stress, inflammation, and apoptosis and leading to hepatotoxicity and nephrotoxicity as severe adverse effects [ 3 , 4 , 5 ]. Cisplatin accumulates in the liver and kidney over an extended period; hence, there is a high incidence of cisplatin-induced hepatorenal impairment in clinical practice [ 6 ].…”

Single-cell transcriptomics in MI identify Slc25a4 as a new modulator of mitochondrial malfunction and apoptosis-associated cardiomyocyte subcluster

“…C4 exhibited elevated expression levels of Kif26b, Itgbl1, Nox4, Pcdh9, and Xkr4. C5 showed elevated expression levels of mitochondrial transcripts, such as mt-Atp6, mt-Cytb, mt-Co3, and mt-Nd2, indicating a notable mitochondrial malfunction that could trigger CM apoptosis during this stage [25][26][27][28] (Fig. 2c).…”

STING in tumors: a focus on non-innate immune pathways

“…Similarly, cytoplasmic translocation of mtDNA has been detected in many disease states and has been associated with cancer progression ( Liu et al, 2019b ; Piantadosi, 2020 ). In particular, when tumor cells are often subjected to multiple physicochemical insults during treatment, their mitochondrial damage is further aggravated and more mtDNA is released into the cytoplasm ( Cheng et al, 2020 ; Zhu et al, 2022 ). Numerous studies have shown that mtDNA is a potent inducer of cGAS-STING signaling ( Wu et al, 2021b ).…”