title: Mitochondrial import and degradation of amyloid-β peptide.
abstract: Mitochondrial dysfunctions associated with amyloid-β peptide (Aβ) accumulation in mitochondria have been observed in Alzheimer's disease (AD) patients' brains and in AD mice models. Aβ is produced by sequential action of β- and γ-secretases cleaving the amyloid precursor protein (APP). The γ-secretase complex was found in mitochondria-associated endoplasmic reticulum membranes (MAM) suggesting that this could be a potential site of Aβ production, from which Aβ is further transported into the mitochondria. In vitro, Aβ was shown to be imported into the mitochondria through the translocase of the outer membrane (TOM) complex. The mitochondrial presequence protease (PreP) is responsible for Aβ degradation reducing toxic effects of Aβ on mitochondrial functions. The proteolytic activity of PreP is, however, lower in AD brain temporal lobe mitochondria and in AD transgenic mice models, possibly due to an increased reactive oxygen species (ROS) production. Here, we review the intracellular mechanisms of Aβ production, its mitochondrial import and the intra-mitochondrial degradation. We also discuss the implications of a reduced efficiency of mitochondrial Aβ clearance for AD. Understanding the underlying mechanisms may provide new insights into mitochondria related pathogenesis of AD and development of drug therapy against AD. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Arrhenius Laboratories for Natural Sciences, SE-106 91 Stockholm, Sweden.
authors.forename: Catarina Moreira
authors.initials: CM
authors.lastname: Pinho
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Arrhenius Laboratories for Natural Sciences, SE-106 91 Stockholm, Sweden. Electronic address: pedro@dbb.su.se.
authors.forename: Pedro Filipe
authors.initials: PF
authors.lastname: Teixeira
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Arrhenius Laboratories for Natural Sciences, SE-106 91 Stockholm, Sweden. Electronic address: e_glaser@dbb.su.se.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Glaser
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis
chemical_list: D016229:Amyloid beta-Peptides
keywords: Amyloid-β peptide; Degradation; MAM; Mitochondria; PreP; Presequence protease