Electroacupuncture ameliorates neuronal injury by Pink1/Parkin-mediated mitophagy clearance in cerebral ischemia-reperfusion

Abstract

<p class="first" id="d17413861e96">The accumulation of dysfunctional mitochondria induced by the impairment of the autophagy-lysosome pathway (ALP), especially mitophagy is an important cause of cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture (EA) exerts remarkable effects in treating ischemic stroke; however, the detailed mechanism remains unclear. In this study, rats were treated with mitochondrial permeability transition pore (mPTP) opening inhibitor, peroxynitrite (ONOO-) scavenger, or selective inhibitor of mitophagy activation during 2-h middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion in combination with EA treatment. RNA-Seq analysis showed that EA treatment in cerebral I/R was linked to the autophagosome, the PI3K/Akt signaling pathway and metabolic pathways. We found that I/R resulted in significantly mitochondrial function impairments including decreased mitochondrial membrane potential (MMP) and ATP levels, aggregation of damaged mitochondria, excessive nitro/oxidative stress, PI3K/Akt/mTOR-mediated ALP dysfunction and deficiency of Pink1/Parkin-mediated mitophagy clearance. The treatment with EA, cyclosporine-A (CsA, a potent inhibitor of mPTP opening) or FeTMPyP (a type of ONOO- scavenger) could significantly increase MMP and/or ATP levels, improve mitochondrial function and decrease neuronal injury. At the same time, EA also improved ALP dysfunction and the deficiency of mitophagy clearance; however, mitochondrial division inhibitor-1 (Mdivi-1, a selective inhibitor of mitophagy activation) blocked mitophagy clearance and aggravated neuronal injury. Taken together, EA ameliorates nitro/oxidative stress-induced mitochondrial functional damage and decreases the accumulation of damaged mitochondria via Pink1/Parkin-mediated mitophagy clearance to protect cells against neuronal injury in cerebral I/R. </p>