Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation.
Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation.
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DOI：
10.1016/j.devcel.2021.02.022
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发表时间：
2021-03-22
影响因子：
11.8
通讯作者：
Xiao, Bo
中科院分区：
文献类型：
--
作者：
Yang, Wanchun;Pang, Dejiang;Chen, Mina;Du, Chongyangzi;Jia, Lanlan;Wang, Luoling;He, Yunling;Jiang, Wanxiang;Luo, Liping;Yu, Zongyan;Mao, Mengqian;Yuan, Qiuyun;Tang, Ping;Xia, Xiaoqiang;Cui, Yiyuan;Jing, Bo;Platero, Alexander;Liu, Yanhui;Wei, Yuquan;Worley, Paul F.;Xiao, Bo
神经元活动增加能量消耗，需要平衡的生产来维持神经元功能。活动如何与能源生产相结合仍不完全清楚。在这里，我们报告，大黄酸调节线粒体三羧酸循环流量的乙酰辅酶A通过激活丙酮酸脱氢酶（PDH），以增加ATP的生产。Rheb由突触活动和乳酸诱导，并通过其与Tom 20的相互作用动态运输到线粒体基质。线粒体定位的Rheb蛋白是活性诱导的PDH活化和ATP产生所必需的。Rheb的细胞类型特异性功能获得和功能丧失遗传模型揭示了PDH磷酸化/活性、乙酰辅酶A和ATP的相互变化，这些变化在mTORC 1的遗传或药理学操作中并不明显。机制上，Rheb与PDH磷酸酶（PDP）物理结合，增强其活性，并与PDH的催化E1α亚基结合，减少PDH磷酸化并增加其活性。研究结果确定Rheb作为节点，通过Rheb-PDH轴平衡神经元活动和神经能量学。神经元活动与神经能量学相协调。Yang等人证明，Rheb向线粒体基质的动态易位激活不依赖于mTORC 1的丙酮酸脱氢酶（PDH），并介导神经元活性调节的线粒体代谢。他们的发现表明Rheb整合PDH依赖性能量产生和mTORC 1依赖性能量消耗的机制。
Neuronal activity increases energy consumption and requires balanced production to maintain neuronal function. How activity is coupled to energy production remains incompletely understood. Here, we report that Rheb regulates mitochondrial tricarboxylic acid cycle flux of acetyl-CoA by activating pyruvate dehydrogenase (PDH) to increase ATP production. Rheb is induced by synaptic activity and lactate and dynamically trafficked to the mitochondrial matrix through its interaction with Tom20. Mitochondria-localized Rheb protein is required for activity-induced PDH activation and ATP production. Cell-type-specific gain- and loss-of-function genetic models for Rheb reveal reciprocal changes in PDH phosphorylation/activity, acetyl-CoA, and ATP that are not evident with genetic or pharmacological manipulations of mTORC1. Mechanistically, Rheb physically associates with PDH phosphatase (PDP), enhancing its activity and association with the catalytic E1α-subunit of PDH to reduce PDH phosphorylation and increase its activity. Findings identify Rheb as a nodal point that balances neuronal activity and neuroenergetics via Rheb-PDH axis. Neuronal activity is coordinated with neuroenergetics. Yang et al. demonstrate that dynamic translocation of Rheb to mitochondrial matrix activates pyruvate dehydrogenase (PDH) independent of mTORC1 and mediates neuronal-activity-regulated mitochondrial metabolism. Their findings suggest a mechanism by which Rheb integrates PDH-dependent energy production and mTORC1-dependent energy consumption.
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GLUT4 动员支持活跃突触的能量需求。
影响因子：
16.2
作者：
Ashrafi G;Wu Z;Farrell RJ;Ryan TA
通讯作者：
Ryan TA
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1523/jneurosci.0026-12.2012
发表时间：
2012-06-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hall CN;Klein-Flügge MC;Howarth C;Attwell D
通讯作者：
Attwell D
影响因子：
29
作者：
Díaz-García CM;Mongeon R;Lahmann C;Koveal D;Zucker H;Yellen G
通讯作者：
Yellen G
影响因子：
4.8
作者：
Caruso, M;Maitan, MA;Beguinot, F
通讯作者：
Beguinot, F