Sirtuin 5-Mediated Lysine Desuccinylation Protects Mitochondrial Metabolism Following Subarachnoid Hemorrhage in Mice
Sirtuin 5-Mediated Lysine Desuccinylation Protects Mitochondrial Metabolism Following Subarachnoid Hemorrhage in Mice
复制标题
Sirtuin 5 介导的赖氨酸脱琥珀酰化保护小鼠蛛网膜下腔出血后的线粒体代谢
DOI：
10.1161/strokeaha.121.034850
复制
发表时间：
2021-11
期刊：
影响因子：
8.3
通讯作者：
Zhang Xiaohua
中科院分区：
文献类型：
--
作者：
Xiao Zhi-Peng;Lv Tao;Hou Pin-Pin;Manaenko Anatol;Liu Yu;ong;Jin Yichao;Gao Li;Jia Feng;Tian Yang;Li Peiying;Zhang John H;Hu Qin;Zhang Xiaohua
补充数字内容可在正文中找到。背景和目的：SIRT5(Sirtuin 5，Sirtuin 5)是多种代谢酶的脱琥珀酸化产物，在维持能量平衡中起重要作用。本研究的目的是确定SIRT5介导的脱琥珀酸化是否能恢复能量代谢并保护大脑免受蛛网膜下腔出血(SAH)的影响。方法：选用雄性C57BL/6或SIRT5−/−小鼠。采用血管内穿孔SAH模型。用液相色谱-串联质谱仪检测大脑皮层蛋白质赖氨酸琥珀酸化。通过测定脑组织pH值、三磷酸腺苷和活性氧水平来评价脑代谢。在SAH后24小时评估神经细胞死亡和神经行为缺陷。用免疫印迹、免疫组织化学和ELISA法检测SIRT5、柠檬酸合成酶赖氨酸琥珀酸化和三磷酸腺苷合成酶亚基在SAH小鼠和患者体内的表达和脱琥珀酸活性。此外，还研究了白藜芦醇介导的SIRT5激活的益处。结果：SAH后小鼠脑内共有211个赖氨酸琥珀酸化位点在170个蛋白质上差异表达。其中39%的琥珀酸化蛋白定位于线粒体，它们与能量代谢有关。SAH导致SIRT5表达减少，琥珀酸化柠檬酸合成酶和ATP合成酶亚基减少，继而降低脑pH，减少ATP，增加活性氧产生，导致神经细胞死亡和神经功能障碍。SIRT5基因敲除可加重SAH的上述效应。白藜芦醇可激活SIRT5。这种激活伴随着线粒体代谢的恢复和早期脑损伤的减轻，以及柠檬酸合酶和三磷酸腺苷合酶的脱琥珀酸化。结论：蛋白赖氨酸琥珀酸化是SAH后代谢危象的生化标志，通过激活SIRT5阻断赖氨酸琥珀酸化可能是治疗SAH的一种有前景的治疗策略。
Supplemental Digital Content is available in the text. Background and Purpose: Sirt5 (Sirtuin 5) desuccinylates multiple metabolic enzymes and plays an important role in maintaining energy homeostasis. The goal of this study was to determine whether Sirt5-mediated desuccinylation restores the energy metabolism and protects brain against subarachnoid hemorrhage (SAH). Methods: Male C57BL/6 or Sirt5−/− mice were used. The endovascular perforation SAH model was applied. Protein lysine succinylation in the brain cortex was examined using liquid chromatography-tandem mass spectrometry analysis. The brain metabolism was evaluated by measurement of brain pH as well as ATP and reactive oxygen species level. Neuronal cell death and neurobehavioral deficits were assessed 24 hours after SAH. The expression and desuccinylation activity of Sirt5, lysine succinylation of citrate synthase and ATP synthase subunits were investigated by Western blot, immunohistochemistry, and ELISA in SAH mice and patients. Furthermore, the benefits of resveratrol-mediated Sirt5 activation were investigated. Results: A total of 211 lysine succinylation sites were differentially expressed on 170 proteins in mice brain after SAH. Thirty-nine percent of these succinylated proteins were localized in mitochondria and they are related to energy metabolism. SAH caused a decrease of Sirt5 expression and succinylated citrate synthase as well as the subunits of ATP synthase, subsequently lowered brain pH, reduced ATP and increased reactive oxygen species production, leading to neuronal cell death, and neurological deficits. Knockdown of Sirt5 aggravated SAH-induced effects, mentioned above. Administration of resveratrol resulted in activation of Sirt5. The activation was accompanied both with restoration of the mitochondrial metabolism and alleviation of early brain injury as well as with desuccinylating citrate synthase and ATP synthase. Conclusions: Protein lysine succinylation is a biochemical hallmark of metabolic crisis after SAH, and disruption of lysine succinylation through activation of Sirt5 might be a promising therapeutic strategy for the treatment of SAH.
登录
查看更多内容
影响因子：
29
作者：
Cochemé HM;Quin C;McQuaker SJ;Cabreiro F;Logan A;Prime TA;Abakumova I;Patel JV;Fearnley IM;James AM;Porteous CM;Smith RA;Saeed S;Carré JE;Singer M;Gems D;Hartley RC;Partridge L;Murphy MP
通讯作者：
Murphy MP
影响因子：
29
作者：
Corbet, Cyril;Pinto, Adan;Feron, Olivier
通讯作者：
Feron, Olivier
影响因子：
6.9
作者：
Conzen, Catharina;Becker, Katrin;Schubert, Gerrit A.
通讯作者：
Schubert, Gerrit A.
MicroRNA-132 通过保护 MCAO 小鼠的血脑屏障减轻脑损伤
影响因子：
5.3
作者：
Zuo, Xiaokun;Lu, Jianfei;Hu, Qin
通讯作者：
Hu, Qin
SIRT5 调节线粒体赖氨酸琥珀酰组和代谢网络。
影响因子：
29
作者：
Rardin MJ;He W;Nishida Y;Newman JC;Carrico C;Danielson SR;Guo A;Gut P;Sahu AK;Li B;Uppala R;Fitch M;Riiff T;Zhu L;Zhou J;Mulhern D;Stevens RD;Ilkayeva OR;Newgard CB;Jacobson MP;Hellerstein M;Goetzman ES;Gibson BW;Verdin E
通讯作者：
Verdin E