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Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
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The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial

Camilla A Hansson Petersen1, Nyosha Alikhani, Homira Behbahani

  • 1Karolinska Institutet Dainippon Sumitomo Pharma Alzheimer Center, NVS, Novum, 141 57 Huddinge, Sweden.

Proceedings of the National Academy of Sciences of the United States of America
|September 2, 2008
PubMed

Insights

Amyloid beta-peptide (Abeta) enters mitochondria via the translocase of the outer membrane (TOM) machinery, independent of membrane potential. This peptide accumulates in mitochondrial cristae, offering insights into Alzheimer

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Amyloid beta-peptide (Abeta) toxicity is linked to intracellular effects.
  • Abeta accumulation in mitochondria negatively impacts mitochondrial function.
  • The mechanism of Abeta's mitochondrial uptake remains unclear.

Purpose of the Study:

  • Investigate the mechanisms of mitochondrial Abeta uptake.
  • Determine the localization of Abeta within mitochondria.
  • Explore the relevance of Abeta mitochondrial localization in neurodegenerative diseases.

Main Methods:

  • In vitro studies using isolated rat mitochondria.
  • Mitochondrial import assays with Abeta.
  • Valinomycin sensitivity assays to assess membrane potential dependence.
  • Subfractionation and immunoelectron microscopy for Abeta localization.
  • Analysis of human cortical brain biopsies.
  • Cellular uptake studies with human neuroblastoma cells.

Main Results:

  • Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery.
  • Mitochondrial import of Abeta is independent of the mitochondrial membrane potential.
  • Abeta localizes to the mitochondrial cristae, both in vitro and in vivo.
  • Extracellular Abeta is internalized by neuroblastoma cells and co-localizes with mitochondrial markers.
  • Similar Abeta distribution observed in human brain biopsies.

Conclusions:

  • A novel mechanism for Abeta mitochondrial import has been identified.
  • Abeta's presence in mitochondrial cristae provides new insights into its pathogenic role.
  • Findings contribute to understanding Abeta's significance in Alzheimer's disease pathogenesis.

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