Mitochondrial Amyloid Beta accumulation via non-canonical receptor Tom22

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Compelling evidence has suggested that mitochondrial dysfunction is an early event in Alzheimer’s Disease (AD) pathophysiology. This mitochondrial dysfunction is closely related to the elevated level of intracellular Aβ, which appears to be accumulated within mitochondria in the brains of both Alzheimer’s patients and mouse models. How mitochondria actively accumulate Aβ is not clear, and thus represents a large gap of knowledge in the field. We aim to understand the very first step of this accumulation process by studying the detailed molecular mechanism of substrate/receptor interaction. We have identified that Aβ is recognized by a non-canonical receptor, Tom22, within the mitochondrial protein import machinery. In this proposal, we expect to perform two related but independent specific aims to reach that goal. 1). We will characterize the interaction between Aβ and Tom22 receptor in details, by biophysical, biochemical and cell biology tools; 2). We expect to determine three dimensional atomic structures of Tom22 and Tom22/Aβ complex. The functional and structural information gained here are expected to reveal detailed molecular mechanism underlining the detrimental process of mitochondrial uptake of Aβ peptides, and thus provide novel models to screen molecules that are capable of disrupting the specific Tom22/Aβ interaction. Thus, the outcome of this proposal is expected to have important positive impact in treating mitochondrial dysfunction caused by Aβ in AD.