title: Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons.
abstract: 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 (Drp1(K38A)) 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 Drp1(K38A). Thus, persistent mitochondrial fission may play a causal role in NO-mediated neurotoxicity.
authors.affiliation: Apoptosis and Cell Death Program, Burnham Institute for Medical Research, La Jolla, CA, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Barsoum
authors.forename: Hua
authors.initials: H
authors.lastname: Yuan
authors.forename: Akos A
authors.initials: AA
authors.lastname: Gerencser
authors.forename: Géraldine
authors.initials: G
authors.lastname: Liot
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kushnareva
authors.forename: Simone
authors.initials: S
authors.lastname: Gräber
authors.forename: Imre
authors.initials: I
authors.lastname: Kovacs
authors.forename: Wilson D
authors.initials: WD
authors.lastname: Lee
authors.forename: Jenna
authors.initials: J
authors.lastname: Waggoner
authors.forename: Jiankun
authors.initials: J
authors.lastname: Cui
authors.forename: Andrew D
authors.initials: AD
authors.lastname: White
authors.forename: Blaise
authors.initials: B
authors.lastname: Bossy
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Martinou
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
authors.forename: Ella
authors.initials: E
authors.lastname: Bossy-Wetzel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D034281:Dynamins / Q000502:physiology*; D004734:Energy Metabolism; D005609:Free Radicals / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure*; D024101:Mitochondrial Proteins / Q000502:physiology*; D009474:Neurons / Q000648:ultrastructure*; D009569:Nitric Oxide / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D020521:Stroke / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D005609:Free Radicals; D008565:Membrane Proteins; C489709:Mfn1 protein, rat; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D012402:Rotenone; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; D034281:Dynamins