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

• Published in: Nature communications Vol. 11; no. 1; pp. 5731 - 13
• Main Authors: Cen, Xufeng, Chen, Yanying, Xu, Xiaoyan, Wu, Ronghai, He, Fusheng, Zhao, Qingwei, Sun, Qiming, Yi, Cong, Wu, Jie, Najafov, Ayaz, Xia, Hongguang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.11.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 38; 49; 631/154/1435/2163; 631/378/1689/1283; 631/80/39/2348; 64/60; 82/83; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Apoptosis; Apoptosis - drug effects; Autophagy-Related Protein 5 - economics; Cell Survival; Disease Models, Animal; Drug development; Drugs; Gene Knockout Techniques; Glucose; HEK293 Cells; HeLa Cells; High-Throughput Screening Assays; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins; Libraries; Male; Mcl-1 protein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins - metabolism; Mitophagy; Mitophagy - drug effects; Mitophagy - physiology; multidisciplinary; 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; Neurodegenerative diseases; Neurons - metabolism; Oxygen; Phenotypes; Presenilin 1; Receptors; Receptors, Cytoplasmic and Nuclear; Science; Science (multidisciplinary); Sulfonamides - pharmacology; Therapeutic targets; Thioglycolates - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19547-6

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. Previous work suggests that mitophagy in neurons is could be therapeutic in Alzheimer’s disease (AD). Here, the authors screen a library of drugs and identify UMI-77, a mitophagy inducer with beneficial effects in an AD mouse model, by binding MCL-1, which they identify as a mitophagy receptor.