Electroacupuncture inhibited neuronal apoptosis through PGAM5/FUNDC1-dependent mitophagy after ischemic stroke

Abstract Neuronal apoptosis persists throughout ischemic stroke. This leads to massive neuron loss and severely impairs recovery of neurological function. Clinical evidence has confirmed that electroacupuncture (EA) effectively improves neurological function after ischemic stroke; however, the underlying mechanism remains to be fully elucidated. In this study, we found that apoptosis and autophagy were activated after ischemic stroke. EA further upregulated autophagy and inhibited neuronal apoptosis in the ischemic stroke model. Furthermore, EA’s neuroprotective effect was linked to mitophagy activation by upregulating PGAM5 expression, which promoted FUNDC1 dephosphorylation and enhanced the interaction between FUNDC1 and LC3, ultimately activating PGAM5/FUNDC1-dependent mitophagy. Enhanced mitochondrial autophagy reduced ROS production and Cyt c release from damaged mitochondria, thereby inhibiting Caspase3 activation and subsequent neuronal apoptosis. Meanwhile, EA also upregulated the level of FUNDC1 and further promoted mitophagy through the PGAM5/FUNDC1 pathway. Notably, lateral ventricle injection of 3-MA inhibited mitophagy and significantly reversed the neuroprotective effect of EA. In summary, the neuroprotective effect of EA against ischemic stroke might be achieved by inhibiting neuronal apoptosis through PGAM5/FUNDC1-dependent mitophagy.