Proceedings of the National Academy of Sciences - PNAS, 2008-09, Vol.105 (35), p.13145-13150
2008
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- Autor(en) / Beteiligte
- Titel
- amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2008-09, Vol.105 (35), p.13145-13150
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2008
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The amyloid β-peptide (Aβ) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Aβ and accumulation of Aβ has been detected in mitochondria. Because Aβ is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial Aβ uptake. Our results from rat mitochondria show that Aβ 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 Aβ association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Aβ to mitochondrial cristae. A similar distribution pattern of Aβ 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 Aβ in mitochondria and demonstrate both in vitro and in vivo that Aβ is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied Aβ can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of Aβ, a peptide considered to be of major significance in Alzheimer's disease.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424, 1091-6490eISSN: 1091-6490DOI: 10.1073/pnas.0806192105Titel-ID: cdi_crossref_primary_10_1073_pnas_0806192105
- Format
- –
- Schlagworte
- Alzheimer disease, Alzheimers disease, Amyloid beta-Peptides - metabolism, Amyloid beta-Peptides - pharmacology, Amyloid beta-Peptides - ultrastructure, Amyloids, Animals, Antibodies, Biochemistry, Biokemi, Biologi, Biological Sciences, Biology, Cell and molecular biology, Cell biology, Cell Line, Tumor, Cell- och molekylärbiologi, Cellbiologi, Chemistry, Cytometry, Endocytosis - drug effects, Endopeptidase K - pharmacology, Extracellular Space - drug effects, Extracellular Space - metabolism, Flow Cytometry, Fluorescent Antibody Technique, human brain biopsies, Humans, Imports, Kemi, Male, MEDICIN, Medicin och hälsovetenskap, MEDICINE, Microscopy, Microscopy, Immunoelectron, Mitochondria, Mitochondria - drug effects, Mitochondria - metabolism, Mitochondria - ultrastructure, Mitochondria, Liver - drug effects, Mitochondria, Liver - metabolism, Mitochondrial Proteins - metabolism, NATURAL SCIENCES, NATURVETENSKAP, Neuroblastoma - metabolism, Neurons, P branes, Pathology, Patologi, Peptides - metabolism, Peptides - pharmacology, protein import, Protein precursors, Protein Transport - drug effects, Rats, Rats, Sprague-Dawley