Aluminum as an inducer of the mitochondrial permeability transition

J Biol Inorg Chem. 2000 Oct;5(5):612-23. doi: 10.1007/s007750000144.

Abstract

Treatment of rat liver mitochondria with aluminum in the presence of Ca2+ results in large amplitude swelling accompanied by loss of endogenous Mg2+ and K+ and oxidation of endogenous pyridine nucleotides. The presence of cyclosporin A, ADP, bongkrekic acid, N-ethylmaleimide and dithioerythritol prevent these effects, indicating that binding of aluminum to the inner mitochondrial membrane, most likely at the level of adenine nucleotide translocase, correlates with the induction of the membrane permeability transition (MPT). Indeed, aluminum binding promotes such a perturbation at the level of ubiquinol-cytochrome c reductase, which favors the production of reactive oxygen species. These metabolites generate an oxidative stress involving two previously defined sites in equilibrium with the glutathione and pyridine nucleotides pools, the levels of which correlate with the increase in MPT induction. Although the above-described phenomena are typical of MPT, they are not paralleled by other events normally observed in response to treatment with inducers of MPT (e.g., phosphate), such as the collapse of the electrochemical gradient and the release of accumulated Ca2+ and oxidized pyridine nucleotides. Biochemical and ultrastructural observations demonstrate that aluminum induces a pore opening having a conformation intermediate between fully open and closed in a subpopulation of mitochondria. While inorganic phosphate enhances the MPT induced by ruthenium red plus a deenergizing agent, aluminum instead inhibits this phenomenon. This finding suggests the presence of a distinct binding site for aluminum differing from that involved in MPT induction.

MeSH terms

  • Adenosine Diphosphate / pharmacology
  • Aluminum / pharmacology*
  • Animals
  • Atractyloside / analogs & derivatives
  • Atractyloside / pharmacology
  • Biological Transport / drug effects
  • Bongkrekic Acid / pharmacology
  • Calcium / metabolism
  • Cations / metabolism
  • Cyclosporine / pharmacology
  • Dose-Response Relationship, Drug
  • Hydrogen-Ion Concentration
  • Intracellular Membranes / drug effects*
  • Intracellular Membranes / metabolism
  • Membrane Potentials / drug effects
  • Microscopy, Electron
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism*
  • Mitochondria, Liver / ultrastructure
  • Mitochondrial Swelling / drug effects
  • Nucleotides / metabolism
  • Oxidation-Reduction
  • Permeability / drug effects*
  • Phosphates / pharmacology
  • Rats
  • Sucrose / metabolism

Substances

  • Cations
  • Nucleotides
  • Phosphates
  • Bongkrekic Acid
  • Atractyloside
  • Sucrose
  • Adenosine Diphosphate
  • Cyclosporine
  • Aluminum
  • carboxyatractyloside
  • Calcium