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  • The EMBO Journal (2006) 25, 3900 - 3911
  • doi:10.1038/sj.emboj.7601253

Published online: 27 July 2006

Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons

Mark J Barsoum1,3,ab, Hua Yuan1,3,b, Akos A Gerencser1,b, Géraldine Liot1,3, Yulia Kushnareva1,3, Simone Gräber1,3, Imre Kovacs1,3, Wilson D Lee1,3, Jenna Waggoner2, Jiankun Cui3, Andrew D White2, Blaise Bossy1,3, Jean-Claude Martinou4, Richard J Youle5, Stuart A Lipton3, Mark H Ellisman2,6, Guy A Perkins2,6 and Ella Bossy-Wetzel1,3

  1. Apoptosis and Cell Death Program, Burnham Institute for Medical Research, La Jolla, CA, USA
  2. National Center for Microscopy and Imaging Research, School of Medicine, University of California, San Diego, La Jolla, CA, USA
  3. Degenerative Disease Program, Burnham Institute for Medical Research, USA
  4. Department of Cell Biology, University of Geneva, Geneva, Switzerland
  5. Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
  6. Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA

Correspondence to:

Ella Bossy-Wetzel, Apoptosis & Cell Death Program, The Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA. Tel.: +1 858 713 6297; Fax: +1 858 646 3195; E-mail: ebossy-wetzel@burnham.org

aPresent address: Department of Natural Sciences & Mathematics, Johnson C Smith University, 100 Beatties Ford Road, Charlotte, NC 28216, USA

bThese authors contributed equally to this work

Received 24 January 2006; Accepted 22 June 2006

Mitochondria are present as tubular organelles in neuronal projections. Here, we report that mitochondria undergo profound fission in response to nitric oxide (NO) in cortical neurons of primary cultures. Mitochondrial fission by NO occurs long before neurite injury and neuronal cell death. Furthermore, fission is accompanied by ultrastructural damage of mitochondria, autophagy, ATP decline and generation of free radicals. Fission is occasionally asymmetric and can be reversible. Strikingly, mitochondrial fission is also an early event in ischemic stroke in vivo. Mitofusin 1 (Mfn1) or dominant-negative Dynamin related protein 1 (Drp1K38A) inhibits mitochondrial fission induced by NO, rotenone and Amyloid-beta peptide. Conversely, overexpression of Drp1 or Fis1 elicits fission and increases neuronal loss. Importantly, NO-induced neuronal cell death was mitigated by Mfn1 and Drp1K38A. Thus, persistent mitochondrial fission may play a causal role in NO-mediated neurotoxicity.

  • Keywords:

    • Alzheimer's disease,
    • dynamin related protein 1,
    • mitofusin 1,
    • Parkinson's disease,
    • stroke