Cited by 256Alzheimer's disease research and treatmentsMitochondrial Function and PathologyCell death mechanisms and regulation

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Nicastrin, Presenilin, APH-1, and PEN-2 Form Active γ-Secretase Complexes in Mitochondria

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Hansson, Camilla A., Frykman, Susanne, Farmery, Mark R., Tjernberg, Lars O., Nilsberth, Camilla, Pursglove, Sharon E., Ito, Akira, Winblad, Bengt, Cowburn, Richard F., Thyberg, Johan, Ankarcrona, Maria·2004·Journal of Biological Chemistry

DOI 10.1074/jbc.m404500200

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Abstract

Mitochondria are central in the regulation of cell death. Apart from providing the cell with ATP, mitochondria also harbor several death factors that are released upon apoptotic stimuli. Alterations in mitochondrial functions, increased oxidative stress, and neurons dying by apoptosis have been detected in Alzheimer's disease patients. These findings suggest that mitochondria may trigger the abnormal onset of neuronal cell death in Alzheimer's disease. We previously reported that presenilin 1 (PS1), which is often mutated in familial forms of Alzheimer's disease, is located in mitochondria and hypothesized that presenilin mutations may sensitize cells to apoptotic stimuli at the mitochondrial level. Presenilin forms an active gamma-secretase complex together with Nicastrin (NCT), APH-1, and PEN-2, which among other substrates cleaves the beta-amyloid precursor protein (beta-APP) generating the amyloid beta-peptide and the beta-APP intracellular domain. Here we have identified dual targeting sequences (for endoplasmic reticulum and mitochondria) in NCT and showed expression of NCT in mitochondria by immunoelectron microscopy. We also showed that NCT together with APH-1, PEN-2, and PS1 form a high molecular weight complex located in mitochondria. gamma-secretase activity in isolated mitochondria was demonstrated using C83 (alpha-secretase-cleaved C-terminal 83-residue beta-APP fragment from BD8 cells lacking presenilin and thus gamma-secretase activity) or recombinant C100-Flag (C-terminal 100-residue beta-APP fragment) as substrates. Both systems generated an APP intracellular domain, and the activity was inhibited by the gamma-secretase inhibitors l-685,458 or Compound E. This novel localization of NCT, PS1, APH-1, and PEN-2 expands the role and importance of gamma-secretase activity to mitochondria.

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Authors: Hansson, C. A., Frykman, S., Farmery, M. R., Tjernberg, L. O., Nilsberth, C., Pursglove, S. E., Ito, A., Winblad, B., Cowburn, R. F., Thyberg, J., & Ankarcrona, M.
Affiliations: Karolinska Institutet (SE)
The University of Sydney (AU)
Corresponding author: Ankarcrona, Maria
ORCID: Frykman, Susanne
Tjernberg, Lars O.
Winblad, Bengt
Ankarcrona, Maria
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2004-12
Volume: 279
Issue: 49
Pages: 51654-51660
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m404500200
OpenAlex: W2132814291
Cited by: 256
References: 41
Citations by year: 2026: 2 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 5 · 2019: 9 · 2018: 8 · 2017: 7 · 2016: 12 · 2015: 7 · 2014: 10 · 2013: 12 · 2012: 22
FWCI: 12.34
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5792 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords: gamma-secretase, mitochondria, nicastrin, presenilin 1, APH-1, Pen-2, Alzheimer's disease, amyloid precursor protein, APP intracellular domain, mitochondrial targeting sequence, neuronal apoptosis, gamma-secretase inhibitors, compound E
MeSH terms: Adenosine Triphosphate, Alzheimer Disease, Amino Acid Sequence, Animals, Brain, Cholic Acids, Detergents, Electrophoresis, Polyacrylamide Gel, Endoplasmic Reticulum, Golgi Apparatus, Male, Membrane Glycoproteins, Membrane Proteins, Mitochondria, Molecular Sequence Data, Neurons, Peptide Hydrolases, Endopeptidases, Peptides, Subcellular Fractions, Immunoblotting, Signal Transduction, Amyloid beta-Peptides, Microscopy, Immunoelectron, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Rats, Sprague-Dawley, Apoptosis, Protein Structure, Tertiary, Oxidative Stress, Immunoprecipitation, Rats, Presenilin-1, Amyloid Precursor Protein Secretases

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Nicastrin, Presenilin, APH-1, and PEN-2 Form Active γ-Secretase Complexes in Mitochondria

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