Journal
CELL DEATH AND DIFFERENTIATION
Volume 14, Issue 3, Pages 462-471Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4402046
Keywords
nitric oxide; Bcl-2 family proteins; Drp1; Mfn; neurodegeneration
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Funding
- NCRR NIH HHS [P41RR04050] Funding Source: Medline
- NEI NIH HHS [R01 EY05477, R01 EY016164, R01 EY09024] Funding Source: Medline
- NIAID NIH HHS [P01 AI05578, P01 AI055789] Funding Source: Medline
- NICHD NIH HHS [P01 HD29587] Funding Source: Medline
- NINDS NIH HHS [R01 NS047973, R01 NS046994, R01 NS044326, R01 NS44314, R01 NS047456, R01 NS14718] Funding Source: Medline
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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 I-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.
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