title: Amyloid-β peptide induces mitochondrial dysfunction by inhibition of preprotein maturation.
abstract: 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.
authors.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Mossmann
authors.affiliation: Institut für Biochemie und Molekularbiologie, ZBMZ, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: F-Nora
authors.initials: FN
authors.lastname: Vögtle
authors.affiliation: 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.
authors.forename: Asli Aras
authors.initials: AA
authors.lastname: Taskin
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
authors.forename: Pedro Filipe
authors.initials: PF
authors.lastname: Teixeira
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Ring
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Burkhart
authors.affiliation: Institut für Biochemie und Molekularbiologie, ZBMZ, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Burger
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
authors.forename: Catarina Moreira
authors.initials: CM
authors.lastname: Pinho
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Jelena
authors.initials: J
authors.lastname: Tadic
authors.affiliation: Department of Neuroanatomy, University of Freiburg, 79104 Freiburg, Germany; Neurocenter, Department of Neurology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Desiree
authors.initials: D
authors.lastname: Loreth
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, Karolinska Institutet, 14186 Stockholm, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.affiliation: F. Hoffmann-La Roche Ltd., pRED Pharma Research & Early Development, DTA Neuroscience, 4070 Basel, Switzerland.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Metzger
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany; Medinzinisches Proteom Center, 44801 Bochum, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Sickmann
authors.affiliation: Department of Neuroanatomy, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kretz
authors.affiliation: Institut für Biochemie und Molekularbiologie, ZBMZ, University of Freiburg, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Wiedemann
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany.
authors.forename: René P
authors.initials: RP
authors.lastname: Zahedi
authors.affiliation: Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Glaser
authors.affiliation: 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.
authors.forename: Chris
authors.initials: C
authors.lastname: Meisinger
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D016229:Amyloid beta-Peptides; D045726:Metalloproteases; D024101:Mitochondrial Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D029701:Saccharomyces cerevisiae Proteins; D012697:Serine Endopeptidases; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C514899:PREP protein, human; C501750:CYM1 protein, S cerevisiae