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Volume 157, Issue 3

Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction Free

Abstract

The widely used drug diclofenac can cause serious heart, liver and kidney injury, which may be related to its ability to cause mitochondrial dysfunction. Using as a model system, we studied the mechanisms of diclofenac toxicity and the role of mitochondria therein. We found that diclofenac reduced cell growth and viability and increased levels of reactive oxygen species (ROS). Strains increasingly relying on respiration for their energy production showed enhanced sensitivity to diclofenac. Furthermore, oxygen consumption was inhibited by diclofenac, suggesting that the drug inhibits respiration. To identify the site of respiratory inhibition, we investigated the effects of deletion of respiratory chain subunits on diclofenac toxicity. Whereas deletion of most subunits had no effect, loss of either Rip1p of complex III or Cox9p of complex IV resulted in enhanced resistance to diclofenac. In these deletion strains, diclofenac did not increase ROS formation as severely as in the wild-type. Our data are consistent with a mechanism of toxicity in which diclofenac inhibits respiration by interfering with Rip1p and Cox9p in the respiratory chain, resulting in ROS production that causes cell death.

  • Received:
  • Accepted:
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  • Published Online:
Keyword(s): CCCP, carbonylcyanide m-chlorophenylhydrazone , ETC, electron transport chain , MPT, mitochondrial permeability transition , NSAID, non-steroidal anti-inflammatory drug , PDR, pleiotropic drug resistance , pHcyt, cytosolic pH , pHmit, mitochondrial pH and ROS, reactive oxygen species
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2011-03-01
2024-04-25
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Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction
Microbiology 157, 685 (2011); https://doi.org/10.1099/mic.0.044578-0
/content/journal/micro/10.1099/mic.0.044578-0
/content/journal/micro/10.1099/mic.0.044578-0
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