Mitochondrial superoxide production negatively regulates neural progenitor proliferation and cerebral cortical development

Yan Hou, Xin Ouyang, Ruiqian Wan, Heping Cheng, Mark P. Mattson, Aiwu Cheng

Research output: Contribution to journalArticle

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 signalregulated 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.

Original languageEnglish (US)
Pages (from-to)2535-2547
Number of pages13
JournalStem Cells
Volume30
Issue number11
DOIs
StatePublished - Nov 2012

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Keywords

  • cpYFP
  • Extracellular signal-regulated kinases
  • Manganese superoxide dismutase
  • Mitochondrial permeability transition pore
  • Neural progenitor cells
  • Neurospheres
  • Proliferation
  • Self-renewal

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

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