The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae
2008 (English)In: Proceedings of the National Academy of Science of the United States of America, ISSN 0027-8424, Vol. 105, no 35, 13145-13150 p.Article in journal (Refereed) Published
The amyloid beta-peptide (Abeta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Abeta and accumulation of Abeta has been detected in mitochondria. Because Abeta is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial Abeta uptake. Our results from rat mitochondria show that Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed Abeta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Abeta to mitochondrial cristae. A similar distribution pattern of Abeta in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for Abeta in mitochondria and demonstrate both in vitro and in vivo that Abeta is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied Abeta can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of Abeta, a peptide considered to be of major significance in Alzheimer's disease.
Place, publisher, year, edition, pages
2008. Vol. 105, no 35, 13145-13150 p.
Amyloid beta-Protein/*metabolism/pharmacology/ultrastructure, Animals, Cell Line; Tumor, Endocytosis/drug effects, Endopeptidase K/pharmacology, Extracellular Space/drug effects/metabolism, Flow Cytometry, Fluorescent Antibody Technique, Humans, Male, Microscopy; Immunoelectron, Mitochondria/drug effects/*metabolism/ultrastructure, Mitochondria; Liver/drug effects/metabolism, Mitochondrial Proteins/*metabolism, Neuroblastoma/metabolism, Peptides/*metabolism/pharmacology, Protein Transport/drug effects, Rats, Rats; Sprague-Dawley
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell Biology
IdentifiersURN: urn:nbn:se:su:diva-14872DOI: 10.1073/pnas.0806192105ISI: 000259343000093PubMedID: 18757748OAI: oai:DiVA.org:su-14872DiVA: diva2:181392