The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism.
The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism.
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DOI：
10.1038/ncomms5993
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发表时间：
2014-09-26
影响因子：
16.6
通讯作者：
Dasgupta, Biplab
中科院分区：
文献类型：
--
作者：
Pooya, Shabnam;Liu, Xiaona;Kumar, V. B. Sameer;Anderson, Jane;Imai, Fumiyasu;Zhang, Wujuan;Ciraolo, Georgianne;Ratner, Nancy;Setchell, Kenneth D. R.;Yutaka, Yoshida;Jankowski, Michael P.;Dasgupta, Biplab
雪旺细胞（SC）的外周轴突髓鞘形成的先决条件是SC分化，最近的证据表明，从糖酵解到氧化代谢的重编程发生在细胞分化过程中。这种重编程是否对SC分化至关重要，以及调节这种关键代谢转变的基因尚不清楚。在这里，我们表明，肿瘤抑制因子Lkb 1是必不可少的代谢过渡和髓鞘的外周轴突。Lkb 1突变神经的髓鞘化不足和肌肉萎缩导致后肢功能障碍和周围神经病变。Lkb 1-null SC在分化过程中未能最佳地激活线粒体氧化代谢。这种赤字是由Lkb 1调节减少生产的线粒体克雷布斯循环底物柠檬酸盐，细胞脂质的前体。因此，Lkb 1突变小鼠的髓鞘脂质减少。恢复柠檬酸盐部分挽救了Lkb 1突变SC缺陷。因此，在SC分化过程中Lkb 1介导的代谢转变增加了正常髓鞘形成所必需的线粒体代谢和脂肪生成。
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.
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影响因子：
11.8
作者：
Dasgupta, Biplab;Milbrandt, Jeffrey
通讯作者：
Milbrandt, Jeffrey
影响因子：
30.8
作者：
Lappe-Siefke, C;Goebbels, S;Nave, KA
通讯作者：
Nave, KA
影响因子：
56.9
作者：
MONUKI, ES;KUHN, R;LEMKE, G
通讯作者：
LEMKE, G
影响因子：
4
作者：
Leitman, Ellen M.;Tewari, Ambika;Melendez-Vasquez, Carmen V.
通讯作者：
Melendez-Vasquez, Carmen V.
影响因子：
64.8
作者：
Fuenfschilling, Ursula;Supplie, Lotti M.;Mahad, Don;Boretius, Susann;Saab, Aiman S.;Edgar, Julia;Brinkmann, Bastian G.;Kassmann, Celia M.;Tzvetanova, Iva D.;Moebius, Wiebke;Diaz, Francisca;Meijer, Dies;Suter, Ueli;Hamprecht, Bernd;Sereda, Michael W.;Moraes, Carlos T.;Frahm, Jens;Goebbels, Sandra;Nave, Klaus-Armin
通讯作者：
Nave, Klaus-Armin