Amyloid-β peptide induces mitochondrial dysfunction by inhibition of preprotein maturation.
- Mossmann D Institut für Biochemie und Molekularbiologie, ZBMZ, University of Freiburg, 79104 Freiburg, Germany; Trinationales Graduiertenkolleg 1478, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
- Vögtle FN Institut für Biochemie und Molekularbiologie, ZBMZ, University of Freiburg, 79104 Freiburg, Germany.
- Taskin AA Institut für Biochemie und Molekularbiologie, ZBMZ, University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, 79104 Freiburg, Germany.
- Teixeira PF Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
- Ring J Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
- Burkhart JM Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany.
- Burger N Institut für Biochemie und Molekularbiologie, ZBMZ, University of Freiburg, 79104 Freiburg, Germany.
- Pinho CM Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
- Tadic J Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
- Loreth D Department of Neuroanatomy, University of Freiburg, 79104 Freiburg, Germany; Neurocenter, Department of Neurology, University of Freiburg, 79104 Freiburg, Germany.
- Graff C Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, Karolinska Institutet, 14186 Stockholm, Sweden.
- Metzger F F. Hoffmann-La Roche Ltd., pRED Pharma Research & Early Development, DTA Neuroscience, 4070 Basel, Switzerland.
- Sickmann A Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany; Medinzinisches Proteom Center, 44801 Bochum, Germany.
- Kretz O Department of Neuroanatomy, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
- Wiedemann N Institut für Biochemie und Molekularbiologie, ZBMZ, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
- Zahedi RP Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany.
- Madeo F Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
- Glaser E Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
- Meisinger C Institut für Biochemie und Molekularbiologie, ZBMZ, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany. Electronic address: chris.meisinger@biochemie.uni-freiburg.de.
- 2014-09-02
Published in:
- Cell metabolism. - 2014
Alzheimer Disease
Amyloid beta-Peptides
Animals
Brain
Humans
Metalloproteases
Mice
Mice, Inbred C57BL
Mitochondria
Mitochondrial Proteins
Mutation
Proto-Oncogene Proteins
Reactive Oxygen Species
Receptors, G-Protein-Coupled
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Serine Endopeptidases
Superoxide Dismutase
English
Most mitochondrial proteins possess N-terminal presequences that are required for targeting and import into the organelle. Upon import, presequences are cleaved off by matrix processing peptidases and subsequently degraded by the peptidasome Cym1/PreP, which also degrades Amyloid-beta peptides (Aβ). Here we find that impaired turnover of presequence peptides results in feedback inhibition of presequence processing enzymes. Moreover, Aβ inhibits degradation of presequence peptides by PreP, resulting in accumulation of mitochondrial preproteins and processing intermediates. Dysfunctional preprotein maturation leads to rapid protein degradation and an imbalanced organellar proteome. Our findings reveal a general mechanism by which Aβ peptide can induce the multiple diverse mitochondrial dysfunctions accompanying Alzheimer's disease.
- Language
-
- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1016/j.cmet.2014.07.024
- PMID 25176146
- Persistent URL
- https://sonar.ch/global/documents/189429
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