The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism

被引:61
作者
Pooya, Shabnam [1 ]
Liu, Xiaona [2 ]
Kumar, V. B. Sameer [1 ]
Anderson, Jane [1 ]
Imai, Fumiyasu [3 ]
Zhang, Wujuan [4 ]
Ciraolo, Georgianne [5 ]
Ratner, Nancy [2 ]
Setchell, Kenneth D. R. [4 ]
Yutaka, Yoshida [3 ]
Jankowski, Michael P. [6 ]
Dasgupta, Biplab [1 ]
机构
[1] Cincinnati Childrens Hosp Med Ctr, Dept Oncol, Cincinnati, OH 45229 USA
[2] Cincinnati Childrens Hosp Med Ctr, Dept Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA
[3] Cincinnati Childrens Hosp Med Ctr, Dept Dev Biol, Cincinnati, OH 45229 USA
[4] Cincinnati Childrens Hosp Med Ctr, Dept Pathol, Cincinnati, OH 45229 USA
[5] Cincinnati Childrens Hosp Med Ctr, Dept Pathol & Lab Med, Cincinnati, OH 45229 USA
[6] Cincinnati Childrens Hosp Med Ctr, Dept Anesthesia, Cincinnati, OH 45229 USA
来源
NATURE COMMUNICATIONS | 2014年 / 5卷
关键词
SCHWANN-CELLS; ADIPOSE-TISSUE; DIFFERENTIATION; KINASE; OLIGODENDROCYTES; ABNORMALITIES; TRANSCRIPTION; EXPRESSION; NEUROPATHY; OXIDATION;
D O I
10.1038/ncomms5993
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
A prerequisite to myelination of peripheral axons by Schwann cells (SCs) is SC differentiation, and recent evidence indicates that reprogramming from a glycolytic to oxidative metabolism occurs during cellular differentiation. Whether this reprogramming is essential for SC differentiation, and the genes that regulate this critical metabolic transition are unknown. Here we show that the tumour suppressor Lkb1 is essential for this metabolic transition and myelination of peripheral axons. Hypomyelination in the Lkb1-mutant nerves and muscle atrophy lead to hindlimb dysfunction and peripheral neuropathy. Lkb1-null SCs failed to optimally activate mitochondrial oxidative metabolism during differentiation. This deficit was caused by Lkb1-regulated diminished production of the mitochondrial Krebs cycle substrate citrate, a precursor to cellular lipids. Consequently, myelin lipids were reduced in Lkb1-mutant mice. Restoring citrate partially rescued Lkb1-mutant SC defects. Thus, Lkb1-mediated metabolic shift during SC differentiation increases mitochondrial metabolism and lipogenesis, necessary for normal myelination.
引用
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页数:15
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