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Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development

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...

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Autores principales: Zheng, Hong, Yu, Wen-Mei, Shen, Jinhua, Kang, Sumin, Hambardzumyan, Dolores, Li, James Y., Shen, Yuxian, Kenney, Anna M., Chen, Jing, Qu, Cheng-Kui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191298/
https://www.ncbi.nlm.nih.gov/pubmed/30338292
http://dx.doi.org/10.1126/sciadv.aat2681
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author Zheng, Hong
Yu, Wen-Mei
Shen, Jinhua
Kang, Sumin
Hambardzumyan, Dolores
Li, James Y.
Shen, Yuxian
Kenney, Anna M.
Chen, Jing
Qu, Cheng-Kui
author_facet Zheng, Hong
Yu, Wen-Mei
Shen, Jinhua
Kang, Sumin
Hambardzumyan, Dolores
Li, James Y.
Shen, Yuxian
Kenney, Anna M.
Chen, Jing
Qu, Cheng-Kui
author_sort Zheng, Hong
collection PubMed
description 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.
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spelling pubmed-61912982018-10-18 Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development Zheng, Hong Yu, Wen-Mei Shen, Jinhua Kang, Sumin Hambardzumyan, Dolores Li, James Y. Shen, Yuxian Kenney, Anna M. Chen, Jing Qu, Cheng-Kui Sci Adv Research Articles 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. American Association for the Advancement of Science 2018-10-10 /pmc/articles/PMC6191298/ /pubmed/30338292 http://dx.doi.org/10.1126/sciadv.aat2681 Text en Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Zheng, Hong
Yu, Wen-Mei
Shen, Jinhua
Kang, Sumin
Hambardzumyan, Dolores
Li, James Y.
Shen, Yuxian
Kenney, Anna M.
Chen, Jing
Qu, Cheng-Kui
Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development
title Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development
title_full Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development
title_fullStr Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development
title_full_unstemmed Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development
title_short Mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development
title_sort mitochondrial oxidation of the carbohydrate fuel is required for neural precursor/stem cell function and postnatal cerebellar development
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191298/
https://www.ncbi.nlm.nih.gov/pubmed/30338292
http://dx.doi.org/10.1126/sciadv.aat2681
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