This study investigates the therapeutic potential of inducing neuronal mitophagy for Alzheimer's disease. A screen of FDA-approved drugs identified UMI-77, a BH3-mimetic targeting MCL-1, as a potent mitophagy activator at sub-lethal doses. Mechanistic studies revealed MCL-1 as a mitophagy receptor directly binding to LC3A. In vivo studies using an APP/PS1 mouse model demonstrated that UMI-77 effectively reversed molecular and behavioral disease phenotypes by inducing mitophagy. These findings highlight MCL-1 as a potential drug target for Alzheimer's disease treatment.
