Effect of amyloid beta-peptide on permeability transition pore: a comparative study

A potentially central factor in neurodegeneration is the permeability transition pore (PTP). Because of the tissue-specific differences in pore properties, we directly compared isolated brain and liver mitochondria responses to the neurotoxic A beta peptides. For this purpose, the following parameters were examined: mitochondrial membrane potential (Delta Psi m), respiration, swelling, ultrastructural morphology, and content of cytochrome c. Both peptides, A beta(25-35) (50 microM) and A beta(1-40) (2 microM), had a similar toxicity, exacerbating the effects of Ca(2+), although, per se, they did not induce (PTP). In liver mitochondria, A beta led to a drop in Delta Psi m and potentiated matrix swelling and disruption induced by Ca(2+). In contrast, brain mitochondria, exposed to the same conditions, demonstrated a higher capacity to accumulate Ca(2+) before the Delta Psi m drop and a slight increase of mitochondrial swelling compared with liver mitochondria. Furthermore, mitochondrial respiratory state 3 was depressed in the presence of A beta, whereas state 4 was unaltered, resulting in an uncoupling of respiration. In both types of mitochondria, A beta did not affect the content of cytochrome c. The Delta Psi m drop was reversed when Ca(2+) was removed by EGTA or when ADP plus oligomycin was present. Pretreatment with cyclosporin A or ADP plus oligomycin prevented the deleterious effects promoted by A beta and/or Ca(2+). It can be concluded that brain and liver mitochondria show a different susceptibility to the deleterious effect of A beta peptide, brain mitochondria being more resistant to the potentiation by A beta of Ca(2+)-induced PTP.