Mitochondrial pyruvate carrier 1 alleviates hypoxic-ischemic brain injury in rats

Aims: Mitochondrial dysfunction is a critical pathological change in cerebral ischemia. Mitochondrial pyruvate carrier 1 (MPC1) is a mitochondrial inner membrane protein carrier participating in pyruvate transport. The work is aiming to figure out the effect of MPC1 on cerebral ischemia.Main methods: Bilateral internal carotid artery embolization (BICAO) model and oxygen glucose deprivation/ reoxygenation (OGD/R) model were used to simulate cerebral ischemia in vivo and in vitro. The effect of MPC1 on cerebral ischemia was detected by imaging, behavioral test, immunofluorescence, flow cytometry, trans-mission electron microscopy, Western blot and RT-Q-PCR. RNA-sequence (RNA-seq) was applied to explore the potential molecular mechanisms underlying the role of MPC1 in cerebral ischemia.Key finding: After BICAO or OGD/R treatment, MPC1 expression in ischemic cortical neurons was significantly decreased. And MPC1 deficiency significantly reduced cerebral blood flow, decreased locomotion activities and exacerbated neuronal injury. Moreover, MPC1 deficiency obviously aggravated oxidative stress, structural disruption and dysfunction of mitochondria, autophagy and calcium overload of ischemic cortical neurons. Interestingly, MPC1 overexpression remarkably reversed neuronal loss and persisting neuronal deficits induced by OGD. Using RNA-seq, 38 MPC1-associated differentially expressed genes were involved in oxidative stress, autophagy and calcium overload. Our results further confirmed that MPC1 could alleviate autophagy via the PI3K/Akt/mTOR pathway in the ischemic cortical neurons. Significance: MPC1 may exert neuroprotective effects by attenuating oxidative stress, mitochondrial dysfunction, calcium overload and autophagy during cerebral ischemia. MPC1-related genes identified by RNA-seq may be a novel therapeutic target for cerebral ischemia.