Mitochondrial Superoxide Production Negatively Regulates Neural Progenitor Proliferation and Cerebral Cortical Development§

Authors

  • Yan Hou,

    1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
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  • Xin Ouyang,

    1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
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  • Ruiqian Wan,

    1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
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  • Heping Cheng,

    1. Institute of Molecular Medicine and National Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China
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  • Mark P. Mattson,

    Corresponding author
    1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
    2. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205
    • Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 251 Bayview Blvd, Baltimore, Maryland 21224, USA
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    • Telephone: 410 558-8463; Fax: 410 558-8465

  • Aiwu Cheng

    Corresponding author
    1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224
    • Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 251 Bayview Blvd, Baltimore, Maryland 21224, USA
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    • Telephone: 410 558-8520; Fax: 410 558-8465


  • Author contributions: Y.H., M.P.M., and A.C.: designed the study; Y.H., X.O., R.W., and A.C.: performed the experiments; Y.H. and A.C.: analyzed the data; H.C.: contributed reagents; Y.H, H.C., M.P.M., and A.C.: wrote the manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS September 4, 2012.

Abstract

Although high amounts of reactive oxygen species (ROS) can damage cells, ROS can also play roles as second messengers, regulating diverse cellular processes. Here, we report that embryonic mouse cerebral cortical neural progenitor cells (NPCs) exhibit intermittent spontaneous bursts of mitochondrial superoxide (SO) generation (mitochondrial SO flashes) that require transient opening of membrane permeability transition pores (mPTP). This quantal SO production negatively regulates NPC self-renewal. Mitochondrial SO scavengers and mPTP inhibitors reduce SO flash frequency and enhance NPC proliferation, whereas prolonged mPTP opening and SO generation increase SO flash incidence and decrease NPC proliferation. The inhibition of NPC proliferation by mitochondrial SO involves suppression of extracellular signal-regulated kinases. Moreover, mice lacking SOD2 (SOD2−/− mice) exhibit significantly fewer proliferative NPCs and differentiated neurons in the embryonic cerebral cortex at midgestation compared with wild-type littermates. Cultured SOD2−/− NPCs exhibit a significant increase in SO flash frequency and reduced NPC proliferation. Taken together, our findings suggest that mitochondrial SO flashes negatively regulate NPC self-renewal in the developing cerebral cortex. STEM CELLS2012;30:2535–2547

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