Tracking mitochondrial Cu(I) fluctuations through a ratiometric fluorescent probe in AD model cells: Towards understanding how AβOs induce mitochondrial Cu(I) dyshomeostasis

Abstract

Mitochondrial copper signaling pathway plays a role in Alzheimer's disease (AD), especially in relevant Amyloid-β oligomers (AβOs) neurotoxicity and mitochondrial dysfunction. Clarifying the relationship between mitochondrial copper homeostasis and both of mitochondrial dysfunction and AβOs neurotoxicity is important for understanding AD pathogenesis. Herein, we designed and synthesized a ratiometric fluorescent probe CHC-NS4 for Cu(I). CHC-NS4 possesses excellent ratiometric response, high selectivity to Cu(I) and specific ability to target mitochondria. Under mitochondrial dysfunction induced by oligomycin, mitochondrial Cu(I) levels gradually increased, which may be related to inhibition of ATP7A-mediated Cu(I) exportation and/or high expression of COX. On this basis, CHC-NS4 was further utilized to visualize the fluctuations of mitochondrial Cu(I) levels during progression of AD model cells induced by AβOs. It was found that mitochondrial Cu(I) levels were gradually elevated during the AD progression, which depended on not only AβOs concentration but also incubation time. Moreover, endocytosis maybe served as a prime pathway mode for mitochondrial Cu(I) dyshomeostasis induced by AβOs during AD progression. These results have provided a novel inspiration into mitochondrial copper biology in AD pathogenesis.

Keywords: Alzheimer's disease; AβOs neurotoxicity; Mitochondrial Cu(I); Mitochondrial dysfunction; Ratiometric fluorescent probe.