PINK1‑regulated mitophagy dysfunction in the pathogenesis of Parkinson's disease (Review)

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the accumulation of misfolded α‑synuclein forming Lewy bodies. Emerging evidence highlights mitochondrial dysfunction as an important and early event in PD pathogenesis. Among the key regulators of mitochondrial quality control, PTEN‑induced kinase 1 (PINK1) plays a pivotal role by initiating mitophagy, the selective clearance of damaged mitochondria. Under physiological conditions, PINK1 is rapidly degraded, whereas mitochondrial depolarization stabilizes PINK1 on the outer mitochondrial membrane, where it recruits and activates Parkin, an E3 ubiquitin ligase, to promote mitophagy. Loss‑of‑function mutations in PINK1 also disrupt this process, leading to the accumulation of dysfunctional mitochondria, oxidative stress, abnormal calcium homeostasis and neuronal apoptosis. Furthermore, PINK1 deficiency has been shown to exacerbate α‑synuclein aggregation, impair synaptic transmission and activate neuroinflammatory pathways, collectively accelerating dopaminergic neurodegeneration. Therapeutic strategies aimed at restoring or enhancing PINK1‑mediated mitophagy through pharmacological activation, gene delivery or modulation of parallel pathways‑represent a promising avenue for PD intervention. Continued elucidation of the molecular functions of PINK1 will provide critical insights into mitochondrial homeostasis and novel therapeutic targets for PD.