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

Microbiology (Reading). 2011 Mar;157(Pt 3):685-694. doi: 10.1099/mic.0.044578-0. Epub 2010 Dec 9.


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 Saccharomyces cerevisiae 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.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / toxicity*
  • Diclofenac / metabolism
  • Diclofenac / toxicity*
  • Electron Transport / physiology
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism*
  • Electron Transport Complex IV / pharmacology
  • Mitochondria / drug effects*
  • Mitochondrial Membranes / metabolism
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / metabolism*
  • Nuclear Pore Complex Proteins / pharmacology
  • Oxygen Consumption / drug effects
  • Oxygen Consumption / physiology
  • Reactive Oxygen Species
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / physiology
  • Saccharomyces cerevisiae / ultrastructure
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Saccharomyces cerevisiae Proteins / pharmacology


  • Anti-Inflammatory Agents, Non-Steroidal
  • NUP42 protein, S cerevisiae
  • Nuclear Pore Complex Proteins
  • Reactive Oxygen Species
  • Saccharomyces cerevisiae Proteins
  • Diclofenac
  • Electron Transport Complex IV