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

Xufeng Cen, Yanying Chen, Xiaoyan Xu, Ronghai Wu, Fusheng He, Qingwei Zhao, Qiming Sun, Cong Yi, Jie Wu (), Ayaz Najafov () and Hongguang Xia ()
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Xufeng Cen: Zhejiang University School of Medicine
Yanying Chen: Zhejiang University School of Medicine
Xiaoyan Xu: Zhejiang University School of Medicine
Ronghai Wu: Zhejiang University School of Medicine
Fusheng He: Taizhou University
Qingwei Zhao: Zhejiang University School of Medicine
Qiming Sun: Zhejiang University School of Medicine
Cong Yi: Zhejiang University School of Medicine
Jie Wu: Taizhou University
Ayaz Najafov: Harvard Medical School
Hongguang Xia: Zhejiang University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19547-6

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