Indomethacin, a Non-steroidal Anti-inflammatory Drug, Develops Gastropathy by Inducing Reactive Oxygen Species-mediated Mitochondrial Pathology and Associated Apoptosis in Gastric Mucosa: A NOVEL ROLE OF MITOCHONDRIAL ACONITASE OXIDATION
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Indomethacin, a Non-steroidal Anti-inflammatory Drug,
Develops Gastropathy by Inducing Reactive Oxygen
Species-mediated Mitochondrial Pathology and Associated
Apoptosis in Gastric Mucosa:
A NOVEL ROLE OF MITOCHONDRIAL ACONITASE OXIDATION
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| Creator |
Maity, Pallab
Bindu, Samik Dey, Sumanta Goya, Manish Alam, Athar Pal, Chinmay Mitra, Kalyan Bandyopadhyay, Uday |
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| Subject |
Infectious Diseases and Immunology
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| Description |
We have investigated the role of mitochondria on the development
of indomethacin (a non-steroidal anti-inflammatory
drug)-induced gastric mucosal apoptosis and associated gastropathy
in rat. Transmission electron microscopic studies indicate
that indomethacin damages mitochondrial ultrastructure
and causes mitochondrial dysfunction as evident from
decreased stage-3 respiration, dehydrogenase activity, and
transmembrane potential (��m). Mitochondrial pathology is
associated with increased generation of intra-mitochondrial-reactive
oxygen species, such as O2 . , H2O2 and �OH, leading to
oxidative stress. O2 . is the most effective to damage mitochondrial
aconitase, leading to the release of iron from its iron-sulfur
cluster. The released iron, by interacting with intra-mitochondrial
H2O2, forms �OH. Immunoprecipitation of mitochondrial
aconitase and subsequent Western immunoblotting indicate
carbonylation of aconitase along with the loss of activity in vivo
after indomethacin treatment. The release of iron has been documented
by fluorescence imaging of mucosal cells by using Phen
Green SK, a specific probe for chelatable iron. Interestingly,
intra-mitochondrial �OH generation is crucial for the development
of mitochondrial pathology and activation of mitochondrial
death pathway by indomethacin. Scavenging of �OH by dimethyl
sulfoxide or �-phenyl-n-tert-butylnitrone, a spin-trap,
prevents indomethacin-induced mitochondrial ultrastructural
changes, oxidative stress, collapse of ��m, and mitochondrial
dysfunction. The scavengers also restore indomethacin-induced
activation of caspase-9 and caspase-3 to block mitochondrial
pathway of apoptosis and gastric mucosal damage. This
study, thus, reveals the critical role of O2 . -mediated mitochondrial
aconitase inactivation to release intra-mitochondrial iron,
which by generating �OHpromotes gastric mucosal cell apoptosis
and gastropathy during indomethacin treatment.
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| Publisher |
American Society for Biochemistry and Molecular Biology
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| Date |
2009
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/192/1/JOURNAL_OF_BIOLOGICAL_CHEMISTRY%2C284(5)_%2C3058%2D3068%2C_2009[115].pdf
Maity, Pallab and Bindu, Samik and Dey, Sumanta and Goya, Manish and Alam, Athar and Pal, Chinmay and Mitra, Kalyan and Bandyopadhyay, Uday (2009) Indomethacin, a Non-steroidal Anti-inflammatory Drug, Develops Gastropathy by Inducing Reactive Oxygen Species-mediated Mitochondrial Pathology and Associated Apoptosis in Gastric Mucosa: A NOVEL ROLE OF MITOCHONDRIAL ACONITASE OXIDATION. The Journal of Biological Chemistry, 284 (5). pp. 3058-3068. |
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| Relation |
http://dx.doi.org/10.1074/jbc.M805329200
http://www.eprints.iicb.res.in/192/ |
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