Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons.
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.
Barsoum
Mark J
MJ
Apoptosis and Cell Death Program, Burnham Institute for Medical Research, La Jolla, CA, USA.
Yuan
Hua
H
Gerencser
Akos A
AA
Liot
Géraldine
G
Kushnareva
Yulia
Y
Gräber
Simone
S
Kovacs
Imre
I
Lee
Wilson D
WD
Waggoner
Jenna
J
Cui
Jiankun
J
White
Andrew D
AD
Bossy
Blaise
B
Martinou
Jean-Claude
JC
Youle
Richard J
RJ
Lipton
Stuart A
SA
Ellisman
Mark H
MH
Perkins
Guy A
GA
Bossy-Wetzel
Ella
E
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
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