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

The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.

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

Open access

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

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1074/jbc.m404500200

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

THE MITOCHONDRIAL DEATH/LIFE REGULATOR IN APOPTOSIS AND NECROSIS
Kroemer, G., Dallaporta, B., & Resche-Rigon, M. (1998) · Annual Review of Physiology · doi:10.1146/annurev.physiol.60.1.619 · Cited by 1,975
ABAD Directly Links Aß to Mitochondrial Toxicity in Alzheimer's Disease
Lustbader, J. W., Cirilli, M., Lin, C., Xu, H. W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., et al. (2004) · Science · doi:10.1126/science.1091230 · Cited by 1,303
Mitochondria
Newmeyer, D. D., & Ferguson-Miller, S. M. (2003) · Cell · doi:10.1016/s0092-8674(03)00116-8 · Cited by 1,272
Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing
Yu, G., Nishimura, M., Arawaka, S., Levitan, D. J., Zhang, L., Tandon, A., Song, Y., Rogaeva, E. A., Chen, F., Kawarai, T., et al. (2000) · Nature · doi:10.1038/35024009 · Cited by 929
Reconstitution of γ-secretase activity
Edbauer, D., Winkler, E., Regula, J. T., Pesold, B., Steiner, H., & Haass, C. (2003) · Nature Cell Biology · doi:10.1038/ncb960 · Cited by 914
Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1
Li, Y.-M., Xu, M., Lai, M.-T., Huang, Q., Castro, J. L., DiMuzio-Mower, J., Harrison, T., Lellis, C., Nadin, A., Neduvelil, J. G., et al. (2000) · Nature · doi:10.1038/35015085 · Cited by 866
γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2
Kimberly, W. T., LaVoie, M. J., Ostaszewski, B. L., Ye, W., Wolfe, M. S., & Selkoe, D. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1037392100 · Cited by 763
Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells
Anandatheerthavarada, H. K., Biswas, G., Robin, M.-A., & Avadhani, N. G. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200207030 · Cited by 571
Brain cytochrome oxidase in Alzheimer's disease
Kish, S. J., Bergeron, C., Rajput, A., Dozic, S., Mastrogiacomo, F., Chang, L., Wilson, J. M., DiStefano, L. M., & Nobrega, J. N. (1992) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1992.tb09439.x · Cited by 537
Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state
Li, Y., Lai, M., Xu, M., Huang, Q., DiMuzio‐Mower, J., Sardana, M. K., Shi, X., Yin, K., Shafer, J. A., & Gardell, S. J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.110126897 · Cited by 523
Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1
Esler, W. P., Kimberly, W. T., Ostaszewski, B. L., Diehl, T. S., Moore, C. L., Tsai, J.-Y., Rahmati, T., Xia, W., Selkoe, D. J., & Wolfe, M. S. (2000) · Nature Cell Biology · doi:10.1038/35017062 · Cited by 514
Electron transport chain defects in Alzheimer's disease brain
Parker, W. D., Parks, J. K., Filley, C. M., & Kleinschmidt-DeMasters, B. K. (1994) · Neurology · doi:10.1212/wnl.44.6.1090 · Cited by 495
Total inactivation of γ–secretase activity in presenilin-deficient embryonic stem cells
Herreman, A., Serneels, L., Annaert, W. G., Collen, D., Schoonjans, L., & Strooper, B. D. (2000) · Nature Cell Biology · doi:10.1038/35017105 · Cited by 481
Amyloid Precursor Protein, Presenilins, and α-Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer’s Disease
Suh, Y.-H., & Checler, F. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.3.469 · Cited by 476
Mice lacking both presenilin genes exhibitearlyembryonic patterningdefectsPreprint
Donoviel, D. B., Hadjantonakis, A., Ikeda, M., Zheng, H., George‐Hyslop, P. S., & Bernstein, A. (1999) · Genes & Development · doi:10.1101/gad.13.21.2801 · Cited by 464
Selective cytotoxicity of intracellular amyloid β peptide1–42 through p53 and Bax in cultured primary human neurons
Zhang, Y., McLaughlin, R., Goodyer, C., & LeBlanc, A. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200110119 · Cited by 418
Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1
Zhang, Z., Nadeau, P. M., Song, W., Donoviel, D. B., Yuan, M., Bernstein, A., & Yankner, B. A. (2000) · Nature Cell Biology · doi:10.1038/35017108 · Cited by 404
Activity-dependent isolation of the presenilin– γ-secretase complex reveals nicastrin and a γ substrate
Esler, W. P., Kimberly, W. T., Ostaszewski, B. L., Ye, W., Diehl, T. S., Selkoe, D. J., & Wolfe, M. S. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052436599 · Cited by 343
Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal Membrane
Pasternak, S., Bagshaw, R. D., Guiral, M., Zhang, S., Ackerley, C. A., Pak, B. J., Callahan, J. W., & Mahuran, D. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304009200 · Cited by 326
PEN-2 Is an Integral Component of the γ-Secretase Complex Required for Coordinated Expression of Presenilin and Nicastrin
Steiner, H., Winkler, E., Edbauer, D., Prokop, S., Basset, G., Yamasaki, A., Kostka, M., & Haass, C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200469200 · Cited by 281
Inhibition of Mitochondrial ATP Generation by Nitric Oxide Switches Apoptosis to Necrosis
Leist, M., Single, B., Naumann, H., Fava, E., Simon, B., Kühnle, S., & Nicotera, P. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4514 · Cited by 275
The Glutamatergic System and Alzheimer???s Disease
Butterfield, D. A., & Pocernich, C. B. (2003) · CNS Drugs · doi:10.2165/00023210-200317090-00004 · Cited by 274
Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease
Mecocci, P. (2002) · Archives of Neurology · doi:10.1001/archneur.59.5.794 · Cited by 229
Increased Sensitivity to Mitochondrial Toxin-Induced Apoptosis in Neural Cells Expressing Mutant Presenilin-1 Is Linked to Perturbed Calcium Homeostasis and Enhanced Oxyradical Production
Keller, J. N., Guo, Q., Holtsberg, F. W., Bruce‐Keller, A. J., & Mattson, M. P. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-12-04439.1998 · Cited by 214
Mammalian APH-1 Interacts with Presenilin and Nicastrin and Is Required for Intramembrane Proteolysis of Amyloid-β Precursor Protein and Notch
Lee, S.-F., Shah, S., Li, H., Yu, C., Han, W., & Yu, G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208164200 · Cited by 210
Are Presenilins Intramembrane-Cleaving Proteases? Implications for the Molecular Mechanism of Alzheimer's Disease
Wolfe, M. S., Angeles, J. D. L., Miller, D. D., Xia, W., & Selkoe, D. J. (1999) · Biochemistry · doi:10.1021/bi991080q · Cited by 202
γ-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation
Herreman, A., Gassen, G. V., Bentahir, M., Nyabi, O., Craessaerts, K., Mueller, U., Annaert, W. G., & Strooper, B. D. (2003) · Journal of Cell Science · doi:10.1242/jcs.00292 · Cited by 200
A presenilin dimer at the core of the γ-secretase enzyme: Insights from parallel analysis of Notch 1 and APP proteolysis
Schroeter, E. H., Ilagan, M. X. G., Brunkan, A. L., Hecimovic, S. K., Li, Y., Xu, M., Lewis, H. D., Saxena, M. T., Strooper, B. D., Coonrod, A., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1735338100 · Cited by 197
Presenilin 1 Is Required for Maturation and Cell Surface Accumulation of Nicastrin
Leem, J. Y., Vijayan, S., Han, P., Cai, D., Machura, M., Radomski, K. L., Veselits, M., Xu, H., & Thinakaran, G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200148200 · Cited by 187
Mature Glycosylation and Trafficking of Nicastrin Modulate Its Binding to Presenilins
Yang, D.-S., Tandon, A., Chen, F., Yu, G., Yu, W. H., Arawaka, S., Hasegawa, H. H., Duthie, M., Schmidt, S. D., Ramabhadran, T. V., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110871200 · Cited by 158
Partial Purification and Characterization of γ-Secretase from Post-mortem Human Brain
Farmery, M. R., Tjernberg, L. O., Pursglove, S. E., Bergman, A., Winblad, B. G., & Näslund, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211992200 · Cited by 152
Bimodal Targeting of Microsomal CYP2E1 to Mitochondria through Activation of an N-terminal Chimeric Signal by cAMP-mediated Phosphorylation
Robin, M., Anandatheerthavarada, H. K., Biswas, G., Sepuri, N. B. V., Gordon, D. M., Pain, D., & Avadhani, N. G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203292200 · Cited by 147
Targeting of NH2-terminal–processed Microsomal Protein to Mitochondria: A Novel Pathway for the Biogenesis of Hepatic Mitochondrial P450MT2
Addya, S., Anandatheerthavarada, H. K., Biswas, G., Bhagwat, S. V., Mullick, J., & Avadhani, N. G. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.139.3.589 · Cited by 137
Dual targeting of cytochrome P4502B1 to endoplasmic reticulum and mitochondria involves a novel signal activation by cyclic AMP‐dependent phosphorylation at Ser128
Anandatheerthavarada, H. K., Biswas, G., Mullick, J., Sepuri, N. B. V., Otvos, L., Pain, D., & Avadhani, N. G. (1999) · The EMBO Journal · doi:10.1093/emboj/18.20.5494 · Cited by 132
Proteomic analysis of human lysosomes: Application to monocytic and breast cancer cells
Journet, A., Chapel, A., Kieffer‐Jaquinod, S., Roux‐Dalvai, F., & Garin, J. (2002) · PROTEOMICS · doi:10.1002/1615-9861(200208)2:8 · Cited by 121
Complex N-linked Glycosylated Nicastrin Associates with Active γ-Secretase and Undergoes Tight Cellular Regulation
Kimberly, W. T., LaVoie, M. J., Ostaszewski, B. L., Ye, W., Wolfe, M. S., & Selkoe, D. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204446200 · Cited by 113
Presenilin-1 is located in rat mitochondria
Ankarcrona, M., & Hultenby, K. R. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00735-0 · Cited by 63
Localization of presenilin–nicastrin complexes and γ‐secretase activity to the trans‐Golgi network
Siman, R., & Velji, J. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01616.x · Cited by 60
Analyses of energy metabolism and mitochondrial genome in post-mortem brain from patients with Alzheimer's disease
Reichmann, H., Fhirke, S., Hebenstreit, G. F., Schrubar, H., & Riederer, P. F. (1993) · Journal of Neurology · doi:10.1007/bf00839971 · Cited by 51
Nicastrin is a resident lysosomal membrane protein
Bagshaw, R. D., Pasternak, S., Mahuran, D. J., & Callahan, J. W. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02865-6 · Cited by 47
Presenilin 1 and Presenilin 2 Have Differential Effects on the Stability and Maturation of Nicastrin in Mammalian Brain
Chen, F., Tandon, A., Sanjo, N., Gu, Y., Hasegawa, H., Arawaka, S., Lee, F. J. S., Ruan, X., Mastrangelo, P., Erdebil, S., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210049200 · Cited by 38

Sorted by citations

Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455
A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine
Wallace, D. C. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.110304.095751 · Cited by 3,185
Intracellular amyloid-β in Alzheimer's disease
LaFerla, F. M., Green, K. N., & Oddo, S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2168 · Cited by 1,942
Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression
Manczak, M., Anekonda, T. S., Henson, E., Park, B. S., Quinn, J., & Reddy, P. H. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl066 · Cited by 1,104
Mitochondria in neuroplasticity and neurological disorders
Mattson, M. P., Gleichmann, M., & Cheng, A. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.010 · Cited by 1,081

See all 256

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks