Amyloid β-peptides interfere with mitochondrial preprotein import competence by a co-aggregation process

A{beta} 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 A{beta} peptides and an interference with mitochondrial functions. Nevertheless, the relevance of intracellular A{beta} peptides in the pathophysiology of AD remained controversial. Here, we found that the two major species of A{beta} peptides, in particular A{beta}42, exhibited a strong inhibitory effect on the preprotein import reactions essential for mitochondrial biogenesis. However, A{beta} peptides interacted only weakly with mitochondria and did not affect the inner membrane potential or the structure of the preprotein translocase complexes. A{beta} 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 A{beta}42, correlating with its importance in AD pathology. Our results demonstrate that a direct interference of aggregation-prone A{beta} peptides with mitochondrial protein biogenesis represents a crucial aspect of the pathobiochemical mechanisms contributing to cellular damage in AD.