Mitochondrial H<sub>2</sub>O<sub>2</sub> Is a Central Mediator of Diclofenac-Induced Hepatocellular Injury
Nonsteroidal anti-inflammatory drug (NSAID) use is associated with adverse consequences, including hepatic injury. The detrimental hepatotoxicity of diclofenac, a widely used NSAID, is primarily connected to oxidative damage in mitochondria, which are the primary source of reactive oxygen species (R...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Book |
| Published: |
MDPI AG,
2023-12-01T00:00:00Z.
|
| Subjects: | |
| Online Access: | Connect to this object online. |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Nonsteroidal anti-inflammatory drug (NSAID) use is associated with adverse consequences, including hepatic injury. The detrimental hepatotoxicity of diclofenac, a widely used NSAID, is primarily connected to oxidative damage in mitochondria, which are the primary source of reactive oxygen species (ROS). The primary ROS responsible for inducing diclofenac-related hepatocellular toxicity and the principal antioxidant that mitigates these ROS remain unknown. Peroxiredoxin III (PrxIII) is the most abundant and potent H<sub>2</sub>O<sub>2</sub>-eliminating enzyme in the mitochondria of mammalian cells. Here, we investigated the role of mitochondrial H<sub>2</sub>O<sub>2</sub> and the protective function of PrxIII in diclofenac-induced mitochondrial dysfunction and apoptosis in hepatocytes. Mitochondrial H<sub>2</sub>O<sub>2</sub> levels were differentiated from other types of ROS using a fluorescent H<sub>2</sub>O<sub>2</sub> indicator. Upon diclofenac treatment, PrxIII-knockdown HepG2 human hepatoma cells showed higher levels of mitochondrial H<sub>2</sub>O<sub>2</sub> than PrxIII-expressing controls. PrxIII-depleted cells exhibited higher mitochondrial dysfunction as measured by a lower oxygen consumption rate, loss of mitochondrial membrane potential, cardiolipin oxidation, and caspase activation, and were more sensitive to apoptosis. Ectopic expression of mitochondrially targeted catalase in PrxIII-knockdown HepG2 cells or in primary hepatocytes derived from PrxIII-knockout mice suppressed the diclofenac-induced accumulation of mitochondrial H<sub>2</sub>O<sub>2</sub> and decreased apoptosis. Thus, we demonstrated that mitochondrial H<sub>2</sub>O<sub>2</sub> is a key mediator of diclofenac-induced hepatocellular damage driven by mitochondrial dysfunction and apoptosis. We showed that PrxIII loss results in the critical accumulation of mitochondrial H<sub>2</sub>O<sub>2</sub> and increases the harmful effects of diclofenac. PrxIII or other antioxidants targeting mitochondrial H<sub>2</sub>O<sub>2</sub> could be explored as potential therapeutic agents to protect against the hepatotoxicity associated with NSAID use. |
|---|---|
| Item Description: | 10.3390/antiox13010017 2076-3921 |