Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation

• Published in: Developmental cell Vol. 56; no. 6; pp. 811 - 825.e6
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.03.2021
• Subjects: Animals; Energy Metabolism; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; mitochondria; Mitochondria - metabolism; mTORC1; neuroenergetics; neuronal activity; Neurons - metabolism; Phosphorylation; pyruvate dehydrogenase; Pyruvate Dehydrogenase Complex - genetics; Pyruvate Dehydrogenase Complex - metabolism; Ras Homolog Enriched in Brain Protein - genetics; Ras Homolog Enriched in Brain Protein - metabolism; Rheb; pyruvate dehydrogenase; neuroenergetics; Rheb; mTORC1; neuronal activity; mitochondria
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2021.02.022

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. [Display omitted] •Rheb activates mitochondrial pyruvate dehydrogenase (PDH) to produce energy•Rheb interacts with PDH phosphatases (PDPs) to activate PDH independent of mTORC1•Rheb mediates neuronal-activity-induced PDH activation•Rheb coordinates PDH-dependent neuroenergetics and mTORC1-dependent neuronal functions 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.