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Tracking mitochondrial Cu(I) fluctuations through a ratiometric fluorescent probe in AD model cells: Towards
Qiaowen Zhao1, Liyi Ma1, Siwei Chen2
1Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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.
Insights
Mitochondrial copper levels rise in Alzheimer's disease (AD) models, linked to amyloid-beta oligomers (AβOs) and cell dysfunction. A new probe visualizes this copper imbalance, offering insights into AD pathogenesis.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Mitochondrial copper signaling is implicated in Alzheimer's disease (AD) pathogenesis.
- Amyloid-beta oligomers (AβOs) contribute to neurotoxicity and mitochondrial dysfunction in AD.
- Understanding mitochondrial copper homeostasis is crucial for elucidating AD mechanisms.
Purpose of the Study:
- To investigate the role of mitochondrial copper in AD.
- To develop a tool for visualizing mitochondrial copper changes in AD.
- To explore the relationship between AβOs, mitochondrial dysfunction, and copper.
Main Methods:
- Design and synthesis of a ratiometric fluorescent probe (CHC-NS4) for Cu(I).
- Utilizing CHC-NS4 to monitor mitochondrial Cu(I) levels in cells with induced mitochondrial dysfunction (oligomycin).
- Visualizing mitochondrial Cu(I) fluctuations in AD model cells exposed to AβOs.
Main Results:
- The probe CHC-NS4 demonstrated high selectivity for Cu(I) and targeted mitochondria effectively.
- Mitochondrial Cu(I) levels increased under oligomycin-induced mitochondrial dysfunction.
- Elevated mitochondrial Cu(I) levels were observed during AD progression in AβOs-treated cells, dependent on AβOs concentration and incubation time.
- Endocytosis was suggested as a pathway for AβOs-induced mitochondrial copper dyshomeostasis.
Conclusions:
- Mitochondrial copper dyshomeostasis is a feature of AD progression.
- The fluorescent probe CHC-NS4 is a valuable tool for studying mitochondrial copper biology in AD.
- Findings provide novel insights into the role of mitochondrial copper in AD pathogenesis.
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