Astrocyte-derived lactate aggravates brain injury of ischemic stroke in mice by promoting the formation of protein lactylation

作者：Xiao‐Yi Xiong, Xinru Pan, Xia-Xia Luo, Yufei Wang, Xin‐Xiao Zhang, Su-Hao Yang, Zhanqiong Zhong, Chang Liu, Qiong Chen, Pengfei Wang, Xiaowei Chen, Shuguang Yu, Qingwu Yang · 发表于：Theranostics · 年份：2024 · DOI：10.7150/thno.96375 · 被引用次数：116 · 研究领域：Neurological Disease Mechanisms and Treatments、Neurological Disorders and Treatments、Alzheimer's disease research and treatments

Aim:Although lactate supplementation at the reperfusion stage of ischemic stroke has been shown to offer neuroprotection, whether the role of accumulated lactate at the ischemia phase is neuroprotection or not remains largely unknown.Thus, in this study, we aimed to investigate the roles and mechanisms of accumulated brain lactate at the ischemia stage in regulating brain injury of ischemic stroke.Methods and Results: Pharmacological inhibition of lactate production by either inhibiting LDHA or glycolysis markedly attenuated the mouse brain injury of ischemic stroke.In contrast, additional lactate supplement further aggravates brain injury, which may be closely related to the induction of neuronal death and A1 astrocytes.The contributing roles of increased lactate at the ischemic stage may be related to the promotive formation of protein lysine lactylation (Kla), while the post-treatment of lactate at the reperfusion stage did not influence the brain protein Kla levels with neuroprotection.Increased protein Kla levels were found mainly in neurons by the HPLC-MS/MS analysis and immunofluorescent staining.Then, pharmacological inhibition of lactate production or blocking the lactate shuttle to neurons showed markedly decreased protein Kla levels in the ischemic brains.Additionally, Ldha specific knockout in astrocytes (Aldh1l1 CreERT2 ; Ldha fl/fl mice, cKO) mice with MCAO were constructed and the results showed that the protein Kla level was decreased accompanied by a decrease...