Citrate synthase lysine K215 hypoacetylation contributes to microglial citrate accumulation and pro‐inflammatory functions after traumatic brain injury

Abstract

AbstractAimsThis study aimed to investigate the relationship between microglial metabolism and neuroinflammation by examining the impact of citrate accumulation in microglia and its potential regulation through Cs K215 hypoacetylation.MethodsExperimental approaches included assessing Cs enzyme activity through Cs K215Q mutation and investigating the inhibitory effects of hesperidin, a natural flavanone glycoside, on citrate synthase. Microglial phagocytosis and expression of pro‐inflammatory cytokines were also examined in relation to Cs K215Q mutation and hesperidin treatment.ResultsCs K215Q mutation and hesperidin exhibited significant inhibitory effects on Cs enzyme activity, microglial citrate accumulation, phagocytosis, and pro‐inflammatory cytokine expression. Interestingly, Sirt3 knockdown aggravated microglial pro‐inflammatory functions during neuroinflammation, despite its proven role in Cs deacetylation.ConclusionCs K215Q mutation and hesperidin effectively inhibited microglial pro‐inflammatory functions without reversing the metabolic reprogramming. These findings suggest that targeting Cs K215 hypoacetylation and utilizing hesperidin may hold promise for modulating neuroinflammation in microglia.