Cited by 693Alzheimer's disease research and treatmentsMitochondrial Function and PathologyAutophagy in Disease and Therapy

The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae

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Hansson Petersen, Camilla A., Alikhani, Nyosha, Behbahani, Homira, Wiehager, Birgitta, Pavlov, Pavel F., Alafuzoff, Irina, Leinonen, Ville, Ito, Akira +3 more·2008·Proceedings of the National Academy of Sciences

Abstract

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.

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Crossref · 10.1073/pnas.0806192105

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Authors
Hansson Petersen, C. A., Alikhani, N., Behbahani, H., Wiehager, B., Pavlov, P. F., Alafuzoff, I., Leinonen, V., Ito, A., Winblad, B., Glaser, E., & Ankarcrona, M.
Affiliations
  • *Karolinska Institutet Dainippon Sumitomo Pharma Alzheimer Center, NVS, Novum, 141 57 Huddinge, Sweden;
  • Stockholm University (SE)
  • Karolinska Institutet (SE)
  • Kuopio University Hospital (FI)
  • Department of Neurosurgery, 70211 Kuopio, Finland; and
  • Dainippon Sumitomo Pharma Company Ltd., 564-0053 Osaka, Japan
Venue
Proceedings of the National Academy of Sciences
Published
2008-09-02
Volume
105
Issue
35
Pages
13145-13150
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2170398463
Cited by
693
References
38
Citations by year
2026: 25 · 2025: 34 · 2024: 26 · 2023: 51 · 2022: 43 · 2021: 49 · 2020: 48 · 2019: 36 · 2018: 38 · 2017: 36 · 2016: 35 · 2015: 32 · 2014: 36 · 2013: 32 · 2012: 52
FWCI
26.86
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
amyloid-beta, mitochondrial protein import, TOM complex, translocase of the outer membrane, mitochondrial cristae, mitochondrial dysfunction, Alzheimer's disease, normal pressure hydrocephalus, neuroblastoma cells, mitochondrial membrane potential, valinomycin
MeSH terms
Animals, Endocytosis, Extracellular Space, Flow Cytometry, Fluorescent Antibody Technique, Humans, Male, Mitochondria, Mitochondria, Liver, Neuroblastoma, Peptides, Amyloid beta-Peptides, Microscopy, Immunoelectron, Rats, Sprague-Dawley, Endopeptidase K, Protein Transport, Mitochondrial Proteins, Cell Line, Tumor, Rats

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