Rheb-regulated mitochondrial pyruvate metabolism of Schwann cells linked to axon stability

Jia, Lanlan1; Liao, Maoxing1; Mou, Aidi1; Zheng, Quanzhen2,3; Yang, Wanchun1; Yu, Zongyan2,3; Cui, Yiyuan1; Xia, Xiaoqiang1,3; Qin, Yue1; Chen, Mina1; Xiao, Bo2,3

2021-11-08

10.1016/j.devcel.2021.09.013

DEVELOPMENTAL CELL   影响因子和分区

1534-5807

1878-1551

The metabolic coupling of Schwann cells (SCs) and peripheral axons is poorly understood. Few molecules in SCs are known to regulate axon stability. Using SC-specific Rheb knockout mice, we demonstrate that Rhebregulated mitochondrial pyruvate metabolism is critical for SC-mediated non-cell-autonomous regulation of peripheral axon stability. Rheb knockout suppresses pyruvate dehydrogenase (PDH) activity (independently of mTORC1) and shifts pyruvate metabolism toward lactate production in SCs. The increased lactate causes age-dependent peripheral axon degeneration, affecting peripheral nerve function. Lactate, as an energy substrate and a potential signaling molecule, enhanced neuronal mitochondrial metabolism and energy production of peripheral nerves. Albeit beneficial to injured peripheral axons in the short term, we show that persistently increased lactate metabolism of neurons enhances ROS production, eventually damaging mitochondria, neuroenergetics, and axon stability. This study highlights the complex roles of lactate metabolism to peripheral axons and the importance of lactate homeostasis in preserving peripheral nerves.

SCI

英语

NI论文

通讯

National Natural Science Foundation of China[31530042,31371484] ; Shenzhen Innovation Committee of Science and Technology-Shenzhen Key Laboratory of Gene Transcription and Systems Biology[ZDSYS20200811144002008] ; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions[2021SHIBS0002]

Cell Biology ; Developmental Biology

Cell Biology ; Developmental Biology

WOS:000723630500008

CELL PRESS

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Neurosci & Metab Res, Chengdu 610041, Peoples R China
2.Southern Univ Sci & Technol, Sch Life Sci, Shenzhen Key Lab Gene Regulat & Syst Biol, Shenzhen 518005, Peoples R China
3.Southern Univ Sci & Technol, Sch Life Sci, Dept Biol, Brain Res Ctr, Shenzhen 518005, Peoples R China

Jia, Lanlan,Liao, Maoxing,Mou, Aidi,et al. Rheb-regulated mitochondrial pyruvate metabolism of Schwann cells linked to axon stability[J]. DEVELOPMENTAL CELL,2021,56(21).

Jia, Lanlan.,Liao, Maoxing.,Mou, Aidi.,Zheng, Quanzhen.,Yang, Wanchun.,...&Xiao, Bo.(2021).Rheb-regulated mitochondrial pyruvate metabolism of Schwann cells linked to axon stability.DEVELOPMENTAL CELL,56(21).

Jia, Lanlan,et al."Rheb-regulated mitochondrial pyruvate metabolism of Schwann cells linked to axon stability".DEVELOPMENTAL CELL 56.21(2021).