Maintaining neuronal integrity and functions requires precise mechanisms controlling organelle and protein quality. Alzheimer's disease (AD) is characterized by functional defects in the clearance and recycling of intracellular components. As such, neuronal homeostasis involves autophagy, mitophagy, and apoptosis. Compromised activity in these cellular processes may cause pathological phenotypes of AD. Dysfunction of mitochondria is one of the hallmarks of AD. Mitophagy is a critical mitochondria quality control system, and the impaired mitophagy is observed in AD. Myeloid cell leukemia 1 (MCL1), a member of the pro-survival B-cell lymphoma protein 2 (BCL2) family, is a mitochondria-targeted protein that contributes to maintaining mitochondrial integrity. Mcl1 knockout mice display peri-implantation lethality. The studies on conditional Mcl1 knockout mice demonstrate that MCL1 plays a central role in neurogenesis and neuronal survival during brain development. Accumulating evidence reveals the critical role of MCL1 as a regulator of neuronal autophagy, mitophagy, and survival. In this review, we discuss the emerging neuroprotective function of MCL1 and how dysregulation of MCL1 signaling is involved in the pathogenesis of AD. As the pro-survival BCL2 family of proteins are promising targets of pharmacological intervention with BH3 mimetic drugs, we also discuss the promise of MCL1-targeting therapy in AD.
Keywords: Alzheimer’s disease; Apoptosis; Autophagy; BH3-mimetics; MCL1; Mitochondria; Mitophagy.