umi-77 and Alzheimer-Disease

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.

Topics: Alzheimer Disease; Animals; Apoptosis; Autophagy-Related Protein 5; 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; Mitophagy; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Nerve Tissue Proteins; Neurons; Oxygen; Receptors, Cytoplasmic and Nuclear; Sulfonamides; Thioglycolates