Mitophagy Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Disease-Specific Pathways and Therapeutic Targets

Abstract

Mitophagy is a specific type of autophagy that is crucial for neuronal survival and for the maintenance of mitochondrial quality. Dysfunction of it leads to the progression of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. This review discusses major pathways of mitophagy, including PINK1-Parkin and Parkin-independent pathways, as well as disease-specific alterations in these pathways. Impaired removal of mitochondria promotes oxidative stress, energy failure, protein aggregation, neuroinflammation and neuronal apoptosis. Emerging treatments, such as urolithin A, rapamycin, nicotinamide riboside and gene-based approaches, may restore mitochondrial homeostasis. Nevertheless, the lack of tools to monitor mitophagic activity and disease-specific responses, as well as limited clinical evidence, hinders therapeutic translation. Elucidation of these mechanisms may facilitate the creation of specific therapies for neurodegenerative disorders.