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Action of diclofenac on kidney mitochondria and cells

Lin Eng Ng1, Annette S Vincent, Barry Halliwell

  • 1Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 119260, Singapore.

Biochemical and Biophysical Research Communications
|August 8, 2006
PubMed

Insights

Diclofenac impairs kidney cell energy production by disrupting the malate-aspartate shuttle, significantly reducing ATP synthesis from key substrates. This affects mitochondrial function and cellular energy supply.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Mitochondria are crucial for cellular energy production.
  • The malate-aspartate shuttle facilitates the transport of reducing equivalents into mitochondria.
  • Diclofenac is a nonsteroidal anti-inflammatory drug with known cellular effects.

Purpose of the Study:

  • To investigate the impact of diclofenac on mitochondrial membrane potential and ATP biosynthesis in renal cells.
  • To elucidate the mechanism by which diclofenac affects mitochondrial energy metabolism.
  • To determine the effect of diclofenac on the malate-aspartate shuttle.

Main Methods:

  • Measurement of mitochondrial membrane potential in isolated rat kidney mitochondria and digitonin-permeabilized MDCK cells.
  • Assessment of ATP biosynthesis using succinate, glutamate, and malate as substrates.
  • Enzyme activity assays for NADH dehydrogenase, glutamate dehydrogenase, and malate dehydrogenase.
  • Evaluation of NAD(P)H generation and malate-aspartate shuttle function.

Main Results:

  • Diclofenac dose-dependently reduced mitochondrial membrane potential.
  • ATP biosynthesis from glutamate/malate was more compromised than from succinate.
  • Diclofenac inhibited the malate-aspartate shuttle, decreasing NAD(P)H generation.
  • Diclofenac did not affect the activity of key mitochondrial enzymes like NADH dehydrogenase.

Conclusions:

  • Diclofenac impairs renal cell ATP production by inhibiting the malate-aspartate shuttle.
  • This inhibition reduces the availability of essential substrates for mitochondrial electron transport.
  • Diclofenac's effects on the malate-aspartate shuttle impact cellular energy homeostasis in the kidney.

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