Tetramerization of PKM2 alleviates traumatic brain injury by ameliorating mitochondrial damage in microglia

Abstract

Abstract Background Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events that determine the outcome of TBI, especially neuronal and cognitive function. Studies have suggested that the metabolic characteristics of microglia dictate their inflammatory response. The pyruvate kinase isoform M2 (PKM2), a key glycolytic enzyme, is involved in the regulation of various cellular metabolic processes, including mitochondrial metabolism. This suggests that PKM2 may also participate in the regulation of microglial activation during TBI. Therefore, the present study aimed to evaluate the role of PKM2 in regulating microglial activation and neuroinflammation and its effects on cognitive function following TBI. Methods A controlled cortical impact (CCI) mouse model and inflammation-induced primary mouse microglial cells in vitro were used to investigate the potential effects of PKM2 inhibition and regulation. Results PKM2 was significantly increased during the acute and subacute phases of TBI and was predominantly detected in microglia rather than in neurons. PKM2 inhibition by TEPP46 and shikonin inhibited microglial M1-like activation and attenuated neuroinflammation following TBI. The effects of general inhibition and tetramerization of PKM2 on microglial activation were compared, and we confirmed that the nuclear translocation of PKM2 is required for the generation of the pro-inflammatory microglial M1 phenotype. PKM2 tetramerization effectively transitioned microglial activation to an anti-inflammatory phenotype and maintained normal mitochondrial morphology by enhancing the interaction between PKM2 and mitofusin 2 (MFN2) in pro-inflammatory activated microglia. General inhibition and tetramerization of PKM2 attenuated cognitive function caused by TBI, whereas PKM2 tetramerization exhibited a better treatment effect. Conclusion Our experiments demonstrated the non-metabolic role of PKM2 in the regulation of microglial activation following TBI. Tetramerization or suppression of PKM2 can prevent the pro-inflammatory M1 microglia phenotype and improve cognitive function after TBI.