This review integrates recent structural and biochemical advances to explain how PINK1 activates Parkin and how PINK1/Parkin-mediated mitophagy is regulated and integrated with other cellular stress responses.

By defining molecular determinants and regulatory nodes in the PINK1/Parkin pathway, the paper highlights actionable targets and mechanisms for drug discovery, biomarker development, and therapies aimed at restoring mitochondrial quality control in Parkinson's disease.

PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration into broader cellular signaling networks. This review synthesizes these insights, focusing on the molecular determinants of PINK1/Parkin activation and the regulatory crosstalk that integrates mitophagy with other cellular stress responses. These mechanistic advances position the PINK1/Parkin pathway as a promising, tractable therapeutic target for Parkinson's disease and related pathologies.