Increasing evidence highlights the protective role of mitophagy in eliminating damaged mitochondria during ischemic stroke. As a mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1) mediates the elimination of damaged mitochondria through mitophagy. However, whether VDAC1 contributes to cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms remain unexplored. In this study, we demonstrated that inhibiting VDAC1 oligomerization reduced infarct volume and improved neurological function following cerebral I/R. We further confirmed that inhibiting VDAC1 oligomerization promoted mitophagy, thereby exerting neuroprotective effects. Additionally, VDAC1 knockdown restored mitochondrial membrane potential and decreased mitochondrial reactive oxygen species generation, thereby alleviating mitochondria damage in neurons subjected to oxygen-glucose deprivation /reoxygenation (OGD/R). Mechanistically, we identified the interaction between VDAC1 oligomers and Lon protease 1 (LONP1) as a critical regulator of mitophagy during cerebral I/R injury. Taken together, our findings provide novel insights into the regulation of mitophagy in cerebral I/R injury and suggest that VDAC1 represents a promising therapeutic target for ischemic stroke.
