Lactylation of nuclear receptor coactivator 4 promotes ferritinophagy and glycolysis of neuronal cells after cerebral ischemic injury.

IF 1.6 4区 医学 Q4 NEUROSCIENCES Neuroreport Pub Date : 2024-10-02 Epub Date: 2024-07-24 DOI:10.1097/WNR.0000000000002080
Xiaoyin He, Zhenzhen Wang, Qingbo Ge, Shuyu Sun, Ruru Li, Baoping Wang
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Abstract

Ischemic stroke remains a major cause of disability and mortality. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy is involved in cerebral ischemic injury. Additionally, lactylation regulates the progression of ischemia injury. This study aimed to investigate the impact of NCOA4 on ferritinophagy and glycolysis of hippocampal neuron cells and its lactylation modification. Middle cerebral artery occlusion (MCAO) mouse and oxygen-glucose deprivation (OGD)-treated HT22 cell models were generated. Ferritinophagy was evaluated via detecting ferrous iron (Fe 2+ ), glutathione, malondialdehyde, and protein levels. Glycolysis was assessed by examining the glucose consumption, lactate production, and extracellular acidification rate. The lactylation was evaluated using immunoprecipitation and immunoblotting. Brain injury in vivo was analyzed by measuring brain infarct and neurological function. The results showed that NCOA4 expression was increased in the blood of patients with acute ischemia stroke, the peri-infarct region of the brain in MCAO mice (increased percentage: 142.11%) and OGD-treated cells (increased percentage: 114.70%). Knockdown of NCOA4 inhibited ferritinophagy and glycolysis of HT22 cells induced by OGD. Moreover, OGD promoted the lactylation of NCOA4 at lysine (K)450 sites, which enhanced NCOA4 protein stability. Additionally, interfering with NCOA4 attenuated brain infarction and neurological dysfunction in MCAO mice. Lactylation of NCOA4 at K450 sites promotes ferritinophagy and glycolysis of hippocampal neuron cells, thereby accelerating cerebral ischemic injury. These findings suggest a novel pathogenesis of ischemic stroke.

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核受体辅激活子 4 的乳化作用可促进脑缺血损伤后神经细胞的铁蛋白吞噬和糖酵解。
缺血性中风仍然是导致残疾和死亡的主要原因。核受体辅激活子 4(NCOA4)介导的噬铁蛋白参与了脑缺血损伤。此外,乳酸化还能调节缺血损伤的进展。本研究旨在探讨 NCOA4 对海马神经元细胞噬铁素和糖酵解的影响及其乳化修饰。研究人员制作了大脑中动脉闭塞(MCAO)小鼠和氧-葡萄糖剥夺(OGD)处理的HT22细胞模型。通过检测亚铁(Fe2+)、谷胱甘肽、丙二醛和蛋白质水平来评估铁蛋白吞噬作用。糖酵解是通过检测葡萄糖消耗、乳酸生成和细胞外酸化率来评估的。使用免疫沉淀和免疫印迹法对乳酸化进行了评估。通过测量脑梗塞和神经功能来分析体内脑损伤。结果显示,NCOA4在急性缺血性脑卒中患者血液、MCAO小鼠脑梗死周围区域(增加百分比:142.11%)和OGD处理细胞(增加百分比:114.70%)中的表达均有所增加。敲除 NCOA4 可抑制 OGD 诱导的 HT22 细胞的噬铁蛋白和糖酵解。此外,OGD 促进了 NCOA4 在赖氨酸(K)450 位点的乳化,从而增强了 NCOA4 蛋白的稳定性。此外,干扰 NCOA4 可减轻 MCAO 小鼠的脑梗塞和神经功能障碍。NCOA4在K450位点的乳化促进了海马神经元细胞的铁蛋白吞噬和糖酵解,从而加速了脑缺血损伤。这些发现提示了缺血性中风的新发病机制。
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来源期刊
Neuroreport
Neuroreport 医学-神经科学
CiteScore
3.20
自引率
0.00%
发文量
150
审稿时长
1 months
期刊介绍: NeuroReport is a channel for rapid communication of new findings in neuroscience. It is a forum for the publication of short but complete reports of important studies that require very fast publication. Papers are accepted on the basis of the novelty of their finding, on their significance for neuroscience and on a clear need for rapid publication. Preliminary communications are not suitable for the Journal. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool. The core interest of the Journal is on studies that cast light on how the brain (and the whole of the nervous system) works. We aim to give authors a decision on their submission within 2-5 weeks, and all accepted articles appear in the next issue to press.
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