@article {Cenini050617, author = {Giovanna Cenini and Cornelia R{\"u}b and Michael Bruderek and Wolfgang Voos}, title = {Amyloid β-peptides interfere with mitochondrial preprotein import competence by a co-aggregation process}, elocation-id = {050617}, year = {2016}, doi = {10.1101/050617}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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 negative effect on the preprotein import reactions essential for mitochondrial protein biogenesis. However, Aβ peptides only weakly interact 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 specific 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 Abbreviations TMRE, tetramethylrhodamine ethyl ester; TCA, trichloroacetic acid; MPP, mitochondrial processing peptidase; BN-PAGE, blue-native polyacrylamide gel electrophoresis; SDS-PAGE, sodiumdodecylsulfate polyacrylamide gel electrophoresis; TOM, translocase of the outer membrane; TIM, translocase of the inner membrane; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; IMS, intermembrane space; DHFR, dihydrofolate reductase; AA, amino acid; ΔΨmt, electric potential across the inner mito-chondrial membrane.}, URL = {https://www.biorxiv.org/content/early/2016/05/04/050617}, eprint = {https://www.biorxiv.org/content/early/2016/05/04/050617.full.pdf}, journal = {bioRxiv} }