American Chemical Society
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Peptide-Conjugated Probe Inducing Mitochondrial Dysfunction and Self-Reporting Cell Apoptosis by Aggregated Proteins

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journal contribution
posted on 2023-08-18, 14:33 authored by Bochao Chen, Jing-Jing Hu, Hanzhi Ouyang, Wei Zhang, Jun Dai, Liang Xu, Fan Xia, Xiaoding Lou
Inducing and monitoring cell apoptosis in a real-time manner are crucial for evaluating the therapeutic effect of drugs and avoiding excessive treatment. Although promising advancements have been made to monitor cell apoptosis by assessing cell membrane integrity, the chronic compromise of cellular fitness caused by imbalance proteostasis is not visible and hard to be detected. As an indicator for cell apoptosis, imaging of aggregated proteins provides a new direction. Herein, we design a peptide-conjugated probe (QRKN) that can induce mitochondrial dysfunction for self-reporting cell apoptosis by imaging aggregated proteins. Specifically, QRKN can be cleaved into the α-helix-forming part (QRK) and azide-modified small-molecule part (N) by overexpressed cathepsin B (CB) in tumor cells. The QRK part can destroy the mitochondrial membrane and promote cytochrome c (Cyt c) efflux and caspase 3 expression. The other N part can inhibit the activity of mitochondrial complex IV (Mito-IV) and decrease the expression level of adenosine triphosphate (ATP). Two signaling pathways cooperatively induce mitochondrial dysfunction, resulting in protein aggregation and cell apoptosis ultimately. Meanwhile, the cell apoptosis process can be monitored based on QRKN, which is highly sensitive to the aggregated protein-triggered viscosity change. The self-reporting probe can monitor therapeutic responses and provide valuable diagnosis information.