Effect of amyloid β‐peptide on permeability transition pore: A comparative study

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Abstract
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 Aβ peptides. For this purpose, the following parameters were examined: mitochondrial membrane potential (ΔΨm), respiration, swelling, ultrastructural morphology, and content of cytochrome c. Both peptides, Aβ25–35 (50 μM) and Aβ1–40 (2 μM), had a similar toxicity, exacerbating the effects of Ca2+, although, per se, they did not induce (PTP). In liver mitochondria, Aβ led to a drop in ΔΨm and potentiated matrix swelling and disruption induced by Ca2+. In contrast, brain mitochondria, exposed to the same conditions, demonstrated a higher capacity to accumulate Ca2+ before the ΔΨm drop and a slight increase of mitochondrial swelling compared with liver mitochondria. Furthermore, mitochondrial respiratory state 3 was depressed in the presence of Aβ, whereas state 4 was unaltered, resulting in an uncoupling of respiration. In both types of mitochondria, Aβ did not affect the content of cytochrome c. The ΔΨm drop was reversed when Ca2+ 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 Aβ and/or Ca2+. It can be concluded that brain and liver mitochondria show a different susceptibility to the deleterious effect of Aβ peptide, brain mitochondria being more resistant to the potentiation by Aβ of Ca2+‐induced PTP.

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