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.
Department of Zoology, University of Coimbra, Coimbra, Portugal.
Paula I
PI
Moreira
Maria S
MS
Santos
António
A
Moreno
A Cristina
AC
Rego
Catarina
C
Oliveira
D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000648:ultrastructure; D002118:Calcium / Q000009:adverse effects*; D019069:Cell Respiration / Q000187:drug effects; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010446:Peptide Fragments / Q000009:adverse effects*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D003574:Cytochrome c Group; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); D002118:Calcium