The irisin-PINK1/Parkin axis plays an essential role in mediating microglial mitophagy: A crucial mechanism for exercise-induced neuroprotection against Parkinson's disease.

The progression of Parkinson's disease (PD) is primarily driven by chronic neuroinflammation in microglia and impaired mitochondrial quality control. Here, we show that 10 weeks of treadmill running ameliorates motor deficits, dopaminergic neuron loss, and α-synuclein (α-syn) pathology in MPTP-induced PD mice. Exercise enhances PINK1/Parkin-dependent mitophagy in microglia, evidenced by increased LC3/Iba1 colocalization, p62 clearance, and direct LC3/Tom20 colocalization, thereby suppressing proinflammatory activation. These effects are mediated by exercise-induced upregulation of FNDC5/irisin. In vitro, recombinant irisin rescues impaired mitophagy and alleviates neuroinflammation in α-syn-exposed microglia. Crucially, pharmacological blockade of irisin receptors with RGDyk abolishes exercise-induced neuroprotection, mitophagy restoration, and behavioral improvements. Our findings reveal: (1) Exercise alleviates PD pathology by enhancing mitochondrial autophagy to reprogram microglial function; (2) Irisin is a key myokine activating microglial mitochondrial autophagy via the PINK1/Parkin pathway; (3) The irisin-mitochondrial autophagy axis represents a novel and promising therapeutic target for PD. This work provides the first evidence that exercise-induced irisin directly regulates microglial mitochondrial homeostasis, establishing a mechanistic basis for exercise-based PD interventions.