TY - JOUR T1 - Amyloid β-peptides interfere with mitochondrial preprotein import competence by a co-aggregation process JF - bioRxiv DO - 10.1101/050617 SP - 050617 AU - Giovanna Cenini AU - Cornelia Rüb AU - Michael Bruderek AU - Wolfgang Voos Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/09/14/050617.abstract N2 - Aβ peptides play a central role in the etiology of Alzheimer disease (AD) by exerting cellular toxicity correlated with aggregate formation. Experimental evidences showed an intraneuronal accumulation of Aβ peptides and an interference with mitochondrial functions. Nevertheless, the relevance of intracellular Aβ peptides in the pathophysiology of AD remained 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 through a extra-mitochondrial co-aggregation mechanism. Co-aggregation and import inhibition were significantly stronger in case of the longer peptide Aβ42, correlating with its importance in AD pathology. Our results demonstrate that a 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.List of AbbreviationsTMREtetramethylrhodamine ethyl esterTCAtrichloroacetic acidMPPmitochondrial processing peptidaseBN-PAGEblue-native polyacrylamide gel electrophoresisSDS-PAGEsodiumdodecylsulfate polyacrylamide gel electrophoresisTOMtranslocase of the outer membraneTIMtranslocase of the inner membraneOMMouter mitochondrial membraneIMMinner mitochondrial membraneIMSintermembrane spaceDHFRdihydrofolate reductaseAAamino acidΔψmtelectric potential across the inner mitochondrial membrane ER -