Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons.
Mitochondrial dysfunction is an underpinning event in many neurodegenerative disorders. Less clear, however, is how mitochondria become injured during neuronal demise. Nitric oxide (NO) evokes rapid mitochondrial fission in cortical neurons. Interestingly, proapoptotic Bax relocates from the cytoplasm into large foci on mitochondrial scission sites in response to nitrosative stress. Antiapoptotic Bcl-xL does not prevent mitochondrial fission despite its ability to block Bax puncta formation on mitochondria and to mitigate neuronal cell death. Mitofusin 1 (Mfn1) or dominant-negative dynamin-related protein 1(K38A) (Drp1(k38A)) inhibits mitochondrial fission and Bax accumulation on mitochondria induced by exposure to an NO donor. Although NO is known to cause a bioenergetic crisis, lowering ATP by glycolytic or mitochondrial inhibitors neither induces mitochondrial fission nor Bax foci formation on mitochondria. Taken together, these data indicate that the mitochondrial fission machinery acts upstream of the Bcl-2 family of proteins in neurons challenged with nitrosative stress.
Yuan
H
H
Apoptosis and Cell Death Program, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Gerencser
A A
AA
Liot
G
G
Lipton
S A
SA
Ellisman
M
M
Perkins
G A
GA
Bossy-Wetzel
E
E
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006019:Glycolysis; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism / Q000502:physiology
D008565:Membrane Proteins; C489709:Mfn1 protein, rat; D024101:Mitochondrial Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D009569:Nitric Oxide; D000255:Adenosine Triphosphate