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; Hongguang Xia

doi:10.1038/s41467-020-19547-6

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

Nat Commun. 2020 Nov 12;11(1):5731. doi: 10.1038/s41467-020-19547-6.

Authors

Xufeng Cen¹, Yanying Chen¹, Xiaoyan Xu¹, Ronghai Wu¹, Fusheng He², Qingwei Zhao³, Qiming Sun¹, Cong Yi¹, Jie Wu⁴, Ayaz Najafov⁵, Hongguang Xia^{6

7

8}

Affiliations

¹ Department of Biochemistry & Molecular Medical Center, Zhejiang University School of Medicine, Hangzhou, 310058, China.
² School of Pharmaceutical and Materials Engineering & Institute for Advanced Studies, Taizhou University, 1139 Shifu Avenue, Taizhou, 318000, China.
³ Research Center for Clinical Pharmacy & Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
⁴ School of Pharmaceutical and Materials Engineering & Institute for Advanced Studies, Taizhou University, 1139 Shifu Avenue, Taizhou, 318000, China. [email protected].
⁵ Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
⁶ Department of Biochemistry & Molecular Medical Center, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
⁷ Research Center for Clinical Pharmacy & Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. [email protected].
⁸ Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / metabolism*
Alzheimer Disease / pathology*
Animals
Apoptosis / drug effects
Autophagy-Related Protein 5 / economics
Cell Survival
Disease Models, Animal
Gene Knockout Techniques
Glucose
HEK293 Cells
HeLa Cells
High-Throughput Screening Assays
Humans
Intracellular Signaling Peptides and Proteins
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microtubule-Associated Proteins / metabolism
Mitophagy / drug effects*
Mitophagy / physiology*
Myeloid Cell Leukemia Sequence 1 Protein / drug effects*
Myeloid Cell Leukemia Sequence 1 Protein / genetics
Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
Neoplasm Proteins
Nerve Tissue Proteins
Neurons / metabolism
Oxygen
Receptors, Cytoplasmic and Nuclear
Sulfonamides / pharmacology
Thioglycolates / pharmacology

Substances

Atg5 protein, mouse
Autophagy-Related Protein 5
Intracellular Signaling Peptides and Proteins
Microtubule-Associated Proteins
Myeloid Cell Leukemia Sequence 1 Protein
NDP52 protein, mouse
Nbr1 protein, mouse
Neoplasm Proteins
Nerve Tissue Proteins
Receptors, Cytoplasmic and Nuclear
Sulfonamides
TAX1BP1 protein, mouse
Thioglycolates
UMI-77
Glucose
Oxygen