Amyloid beta-peptide disrupts mitochondrial membrane lipid and protein structure: protective role of tauroursodeoxycholate.
Mitochondria have been implicated in the cytotoxicity of amyloid beta-peptide (A beta), which accumulates as senile plaques in the brain of Alzheimer's disease patients. Tauroursodeoxycholate (TUDC) modulates cell death, in part, by preventing mitochondrial membrane perturbation. Using electron paramagnetic resonance spectroscopy analysis of isolated mitochondria, we tested the hypothesis that A beta acts locally in mitochondrial membranes to induce oxidative injury, leading to increased membrane permeability and subsequent release of caspase-activating factors. Further, we intended to determine the role of TUDC at preventing A beta-induced mitochondrial membrane dysfunction. The results demonstrate oxidative injury of mitochondrial membranes during exposure to A beta and reveal profound structural changes, including modified membrane lipid polarity and disrupted protein mobility. Cytochrome c is released from the intermembrane space of mitochondria as a consequence of increased membrane permeability. TUDC, but not cyclosporine A, almost completely abrogated A beta-induced perturbation of mitochondrial membrane structure. We conclude that A beta directly induces cytochrome c release from mitochondria through a mechanism that is accompanied by profound effects on mitochondrial membrane redox status, lipid polarity, and protein order. TUDC can directly suppress A beta-induced disruption of the mitochondrial membrane structure, suggesting a neuroprotective role for this bile salt.
Rodrigues
C M
CM
Centro de Patogénese Molecular, Faculdade de Farmácia, University of Lisbon, 1600-083 Lisbon, Portugal.
Solá
S
S
Brito
M A
MA
Brondino
C D
CD
Brites
D
D
Moura
J J
JJ
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D007425:Intracellular Membranes / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013113:Spin Labels; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D003574:Cytochrome c Group; D008563:Membrane Lipids; D008565:Membrane Proteins; D010446:Peptide Fragments; D013113:Spin Labels; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine