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Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development.
Science Advances ( IF 11.7 ) Pub Date : 2018-Oct-01 , DOI: 10.1126/sciadv.aat2681
Hong Zheng 1, 2 , Wen-Mei Yu 1, 2 , Jinhua Shen 2 , Sumin Kang 3 , Dolores Hambardzumyan 1 , James Y Li 4 , Yuxian Shen 5 , Anna M Kenney 1 , Jing Chen 3 , Cheng-Kui Qu 1, 2
Affiliation  

While deregulation of mitochondrial metabolism and cytosolic glycolysis has been well recognized in tumor cells, the role of coordinated mitochondrial oxidation and cytosolic fermentation of pyruvate, a key metabolite derived from glucose, in physiological processes is not well understood. Here, we report that knockout of PTPMT1, a mitochondrial phosphoinositide phosphatase, completely blocked postnatal cerebellar development. Proliferation of granule cell progenitors, the most actively replicating cells in the developing cerebellum, was only moderately decreased, and proliferation of Purkinje cell progenitors did not seem to be affected in knockout mice. In contrast, generation of functional Bergmann glia from multipotent precursor cells (radial glia), which is essential for cerebellar corticogenesis, was totally disrupted. Moreover, despite a low turnover rate, neural stem cells were impaired in self-renewal in knockout mice. Mechanistically, loss of PTPMT1 decreased mitochondrial aerobic metabolism by limiting utilization of pyruvate, which resulted in bioenergetic stress in neural precursor/stem cells but not in progenitor or mature cells, leading to cell cycle arrest through activation of the AMPK-p19/p21 pathway. This study suggests that mitochondrial oxidation of the carbohydrate fuel is required for postnatal cerebellar development, and identifies a bioenergetic stress-induced cell cycle checkpoint in neural precursor/stem cells.

中文翻译:


碳水化合物燃料的线粒体氧化是神经前体/干细胞功能和出生后小脑发育所必需的。



虽然在肿瘤细胞中线粒体代谢和胞质糖酵解的失调已得到充分认识,但协调线粒体氧化和丙酮酸(一种源自葡萄糖的关键代谢物)胞质发酵在生理过程中的作用尚不清楚。在这里,我们报告敲除PTPMT1 (一种线粒体磷酸肌醇磷酸酶)完全阻断了出生后小脑的发育。颗粒细胞祖细胞(发育中小脑中复制最活跃的细胞)的增殖仅适度减少,而在基因敲除小鼠中,浦肯野细胞祖细胞的增殖似乎并未受到影响。相比之下,多能前体细胞(放射状胶质细胞)生成的功能性伯格曼胶质细胞(对于小脑皮质生成至关重要)却被完全破坏。此外,尽管更新率较低,但基因敲除小鼠的神经干细胞自我更新能力受到损害。从机制上讲,PTPMT1 的缺失通过限制丙酮酸的利用来减少线粒体有氧代谢,从而导致神经前体/干细胞而非祖细胞或成熟细胞中产生生物能应激,从而通过激活 AMPK-p19/p21 途径导致细胞周期停滞。这项研究表明碳水化合物燃料的线粒体氧化是出生后小脑发育所必需的,并确定了神经前体/干细胞中生物能应激诱导的细胞周期检查点。
更新日期:2018-10-11
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