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

A beta 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 A beta peptides and interference with mitochondrial functions. Nevertheless, the relevance of intracellular A beta peptides in the pathophysiology of AD is 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 via an extramitochondrial coaggregation mechanism. Coaggregation and import inhibition were significantly stronger for the longer peptide A beta 42, correlating with its importance in AD pathology. Our results demonstrate that 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.