PINK1/PARK2 Mitophagy Enhancement for Microglial Polarization

This hypothesis proposes that direct enhancement of PINK1/PARK2-mediated mitophagy in microglia will shift microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby resolving chronic neuroinflammation through metabolic reprogramming rather than direct inflammasome inhibition. The mechanism centers on mitophagy’s role in controlling microglial metabolic state and phenotypic switching. PINK1 (PTEN-induced kinase 1) accumulates on depolarized mitochondria and phosphorylates ubiquitin and the E3 ligase PARK2 (Parkin) at Ser65, creating a feed-forward amplification loop that recruits PARK2 to damaged mitochondria. PARK2 then ubiquitinates multiple mitochondrial proteins, including VDAC1, Mfn1/2, and TOM20, targeting the entire organelle for autophagosomal engulfment and lysosomal degradation. In microglia, enhanced mitophagy removes damaged, ROS-producing mitochondria that drive M1 polarization through HIF-1α stabilization and glycolytic reprogramming. Simultaneously, mitophagy promotes mitochondrial biogenesis through PGC-1α activation, generating healthy mitochondria that support oxidative metabolism characteristic of the M2 anti-inflammatory state. M2 microglia produce anti-inflammatory mediators including IL-10, TGF-β, and arginase-1, while expressing phagocytic receptors that facilitate debris clearance and tissue repair. This metabolic switch from glycolysis to oxidative phosphorylation fundamentally alters microglial function, promoting neuroprotective rather than neurotoxic activities. The hypothesis predicts that pharmacological PINK1/PARK2 pathway enhancers, mitophagy-inducing compounds like urolithin A or nicotinamide riboside, or genetic overexpression of PINK1/PARK2 will increase mitochondrial turnover, reduce microglial ROS production, and shift the M1/M2 balance toward tissue repair and inflammation resolution in neurodegeneration models.