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

Jolanda S van Leeuwen1, Rick Orij2, Marijke A H Luttik3,4

  • 1LACDR, Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

Microbiology (Reading, England)
|December 15, 2010
PubMed

Insights

The common drug diclofenac harms mitochondria, leading to cell damage. Researchers found it inhibits cellular respiration, causing reactive oxygen species (ROS) production and cell death.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Toxicology

Background:

  • Diclofenac is a widely used drug with known risks of heart, liver, and kidney injury.
  • Mitochondrial dysfunction is a potential mechanism underlying diclofenac toxicity.

Purpose of the Study:

  • To investigate the mechanisms of diclofenac toxicity.
  • To elucidate the role of mitochondria in diclofenac-induced cellular damage using Saccharomyces cerevisiae as a model system.

Main Methods:

  • Assessing diclofenac's impact on cell growth, viability, and reactive oxygen species (ROS) production in yeast.
  • Evaluating the sensitivity of yeast strains with varying reliance on respiration.
  • Measuring oxygen consumption rates.
  • Analyzing the effects of deleting specific respiratory chain subunits (Rip1p and Cox9p) on diclofenac toxicity and ROS levels.

Main Results:

  • Diclofenac reduced yeast cell growth and viability while increasing ROS levels.
  • Yeast strains more dependent on respiration were more sensitive to diclofenac.
  • Diclofenac inhibited oxygen consumption, indicating respiratory chain interference.
  • Deletion of Rip1p (complex III) or Cox9p (complex IV) subunits conferred resistance to diclofenac and reduced ROS accumulation.

Conclusions:

  • Diclofenac toxicity involves the inhibition of cellular respiration, specifically by interfering with respiratory chain complexes III and IV.
  • This respiratory inhibition leads to increased ROS production, contributing to cell death.
  • Mitochondrial dysfunction, particularly in the respiratory chain, is a key factor in diclofenac's adverse effects.

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