Journal of Molecular Biology

PINK1/Parkin-mediated mitophagy is critical for regulating mitochondrial health and neuronal homeostasis.

Mutations in mitophagy-associated genes have been linked to Parkinson's disease and Amyotrophic lateral sclerosis.

Mechanisms of neuronal mitochondrial quality control independent of PINK1/Parkin are now being identified.

Deciphering the intersecting molecular pathways governing mitophagy can reveal new therapies for neurodegenerative diseases.

Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration, and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.

mitophagy

PINK1

Parkin

neurodegeneration

autophagosomes

© 2025 The Author(s). Published by Elsevier Ltd.