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ACS Combinatorial Science

ACS Combinatorial Science

IF: 3.78
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Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model

Published:12 November 2020 DOI: 10.1038/s41467-020-19547-6 PMID: 33184293
Xufeng Cen,?Yanying Chen,?Xiaoyan Xu,?Ronghai Wu,?Fusheng He,?Qingwei Zhao,?Qiming Sun,?Cong Yi,?Jie Wu,?Ayaz Najafov,?Hongguang Xia

Abstract

There is increasing evidence that inducing neuronal mitophagy can be used as a therapeutic intervention for Alzheimer's disease. Here, we screen a library of 2024 FDA-approved drugs or drug candidates, revealing UMI-77 as an unexpected mitophagy activator. UMI-77 is an established BH3-mimetic for MCL-1 and was developed to induce apoptosis in cancer cells. We found that at sub-lethal doses, UMI-77 potently induces mitophagy, independent of apoptosis. Our mechanistic studies discovered that MCL-1 is a mitophagy receptor and directly binds to LC3A. Finally, we found that UMI-77 can induce mitophagy in vivo and that it effectively reverses molecular and behavioral phenotypes in the APP/PS1 mouse model of Alzheimer's disease. Our findings shed light on the mechanisms of mitophagy, reveal that MCL-1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL-1 as a drug target for therapeutic intervention in Alzheimer's disease.

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Materials Related products
Procduct Name CAS Molecular Formula Supplier Price
UMI-77 518303-20-3 C18H14BrNO5S2 116 suppliers $26.00-$3772.00
UMI-77 518303-20-3 C18H14BrNO5S2 116 suppliers $26.00-$3772.00
UMI-77 518303-20-3 C18H14BrNO5S2 116 suppliers $26.00-$3772.00
UMI-77 518303-20-3 C18H14BrNO5S2 116 suppliers $26.00-$3772.00

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