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

Abstract Neuronal apoptosis persists throughout ischemic stroke and leads to massive neuron loss, which severely hampers the recovery of neurological function. Clinical evidence has confirmed that EA effectively improves neurological function after stroke, but the undergoing mechanism still needs to be fully clarified. In this study we found that apoptosis and autophagy were activated after ischemic stroke, howerver EA further upregulated autophagy and inhibit neuronal apoptosis. Furthermore, the neuroprotective effect of EA was associated with the activation of mitophagy. Mechanistically, EA upregulated the expression of PGAM5 to promote FUNDC1 dephosphorylation, and then enhanced the affinity of FUNDC1 with LC3, ultimately activating PGAM5/FUNDC1-dependent mitophagy. Enhanced mitochondrial autophagy reduced the release of ROS and Cytc from damaged mitochondria, inhibited the activation of Caspase3 and subsequent neuronal apoptosis. Meanwhile, it also upregulated the level of FUNDC1 and further promoted mitophagy through the PGAM5/FUNDC1 pathway. Notably, inhibition of mitophagy by lateral ventricle injection of 3-MA significantly reversed the neuroprotective effect of EA. In summary, activating mitophagy by EA to inhibit neuronal apoptosis is a potential mechanism in post-stroke neurorepair.