Mitochondrial accumulation of amyloid β (Aβ) peptides requires TOMM22 as a main Aβ receptor in yeast

Mitochondrial accumulation of intracellular β-amyloid (Aβ) peptides is present in the brains of individuals with Alzheimer's disease (AD) as well as in related mouse models of AD. This accumulation is extremely toxic because Aβ disrupts the normal functions of many mitochondrial proteins, resulting in significant mitochondrial dysfunction. Therefore, understanding the mitochondrial accumulation of Aβ is useful for future pharmaceutical design of drugs to address mitochondrial dysfunction in AD. However, the detailed molecular mechanism of this accumulation process remains elusive. Here, using yeast mitochondria, we present direct experimental evidence suggesting that Aβ is specifically recognized by translocase of outer mitochondrial membrane subunit 22 (Tom22 in yeast; TOMM22 in human), a noncanonical receptor within the mitochondrial protein import machinery, and that this recognition is critical for Aβ accumulation in mitochondria. Furthermore, we found that residues 25-42 in the Aβ peptide mediate the specific interaction with TOMM22. On the basis of our findings, we propose that cytosolic Aβ is recognized by TOMM22; transferred to another translocase subunit, TOMM40; and transported through the TOMM channel into the mitochondria. Our results not only confirm that yeast mitochondria can be used as a model to study mitochondrial dysfunction caused by Aβ peptides in AD but also pave the way for future studies of the molecular mechanism of mitochondrial Aβ accumulation.