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Calcium dysregulation mediates mitochondrial and neurite outgrowth abnormalities in SOD2 deficient embryonic cerebral cortical neurons

Cell Death & Differentiation (2018) | Download Citation


Mitochondrial superoxide dismutase 2 (SOD2) is a major antioxidant defense enzyme. Here we provide evidence that SOD2 plays critical roles in maintaining calcium homeostasis in newly generated embryonic cerebral cortical neurons, which is essential for normal mitochondrial function and subcellular distribution, and neurite outgrowth. Primary cortical neurons in cultures established from embryonic day 15 SOD2+/+ and SOD2−/− mice appear similar during the first 24 h in culture. During the ensuing two days in culture, SOD2−/− neurons exhibit a profound reduction of neurite outgrowth and their mitochondria become fragmented and accumulate in the cell body. The structural abnormalities of the mitochondria are associated with reduced levels of phosphorylated (S637) dynamin related protein 1 (Drp1), a major mitochondrial fission-regulating protein, whereas mitochondrial fusion regulating proteins (OPA1 and MFN2) are relatively unaffected. Mitochondrial fission and Drp1 dephosphorylation coincide with impaired mitochondrial Ca2+ buffering capacity and an elevation of cytosolic Ca2+ levels. Treatment of SOD2−/− neurons with the Ca2+ chelator BAPTA-AM significantly increases levels of phosphorylated Drp1, reduces mitochondrial fragmentation and enables neurite outgrowth.

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This research was supported by the Intramural Research Program of the National Institute on Aging and NSFC (Project 31521062).

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Author notes

  1. These authors contributed equally: Qijin Zhao, Daoyuan Lu.


  1. Laboratory of Neurosciences, Biomedical Research Center, National Institute on Aging Intramural Research Program, 251 Bayview Blvd, Baltimore, MD, 21224, USA

    • Qijin Zhao
    • , Daoyuan Lu
    • , Jing Wang
    • , Mark P. Mattson
    •  & Aiwu Cheng
  2. Laboratory of Calcium Signaling and Mitochondrial Biomedicine, Institute of Molecular Medicine, Peking University, 100871, Beijing, China

    • Qijin Zhao
    • , Beibei Liu
    •  & Heping Cheng
  3. Department of Neuroscience, Johns Hopkins University School Medicine, Baltimore, MD, 21205, USA

    • Mark P. Mattson


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The authors declare that they have no conflict of interest.

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Correspondence to Mark P. Mattson or Aiwu Cheng.

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