title: Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process.
abstract: Aβ peptides play a central role in the etiology of Alzheimer disease (AD) by exerting cellular toxicity correlated with aggregate formation. Experimental evidence has shown intraneuronal accumulation of Aβ peptides and interference with mitochondrial functions. Nevertheless, the relevance of intracellular Aβ peptides in the pathophysiology of AD is controversial. Here we found that the two major species of Aβ peptides, in particular Aβ42, exhibited a strong inhibitory effect on the preprotein import reactions essential for mitochondrial biogenesis. However, Aβ peptides interacted only weakly with mitochondria and did not affect the inner membrane potential or the structure of the preprotein translocase complexes. Aβ peptides significantly decreased the import competence of mitochondrial precursor proteins via an extramitochondrial coaggregation mechanism. Coaggregation and import inhibition were significantly stronger for the longer peptide Aβ42, correlating with its importance in AD pathology. Our results demonstrate that direct interference of aggregation-prone Aβ peptides with mitochondrial protein biogenesis represents a crucial aspect of the pathobiochemical mechanisms contributing to cellular damage in AD.
authors.affiliation: Institut für Biochemie und Molekularbiologie, Universität Bonn, 53115 Bonn, Germany.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenini
authors.affiliation: Institut für Biochemie und Molekularbiologie, Universität Bonn, 53115 Bonn, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rüb
authors.affiliation: Institut für Biochemie und Molekularbiologie, Universität Bonn, 53115 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bruderek
authors.affiliation: Institut für Biochemie und Molekularbiologie, Universität Bonn, 53115 Bonn, Germany wolfgang.voos@uni-bonn.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Voos
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D006367:HeLa Cells; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000503:physiopathology*; D021381:Protein Transport
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D024101:Mitochondrial Proteins