| Translocation of heme oxygenase-1 to mitochondria is a novel cytoprotective mechanism against non-steroidal anti-inflammatory drug-induced mitochondrial oxidative stress, apoptosis and gastric mucosal injury. | |
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MedLine Citation:
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PMID: 21908612 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The mechanism of action of heme oxygenase-1 (HO-1) in mitochondrial oxidative stress (MOS)-mediated apoptotic tissue injury has been investigated. MOS-mediated gastric mucosal apoptosis and injury was introduced in rat by indomethacin, a non-steroidal anti-inflammatory drug. Here, we report that HO-1 is not only induced but also translocated to mitochondria during gastric mucosal injury to favor repair mechanisms. Furthermore, mitochondrial translocation of HO-1 results in the prevention of MOS and mitochondrial pathology as evident from the restoration of complex-I driven mitochondrial respiratory control ratio (RCR) and transmembrane potential (Δψm). Mitochondrial translocation of HO-1 also results in time-dependent inhibition of apoptosis. We searched for the plausible mechanisms responsible for HO-1 induction and mitochondrial localization. Free heme, the substrate for HO-1 is increased inside mitochondria during gastric injury and mitochondrial entry of HO-1 decreases intra-mitochondrial free heme content suggesting a purpose of mitochondrial translocation of HO-1 is to detoxify accumulated heme. Heme may activate nuclear translocation of NF-E2-related factor 2 (Nrf2) to induce HO-1 through reactive oxygen species generation. Electrophoretic mobility shift assay and chromatin immunoprecipitation studies indicated nuclear translocation of Nrf-2 and its binding to HO-1 promoter to induce HO-1 expression during gastric injury. Inhibition of HO-1 by zinc protoporphyrin aggravated the mucosal injury and delayed healing. Zinc protoporphyrin further reduced RCR and Δψm and enhanced MOS and apoptosis. In contrast, induction of HO-1 by cobalt protoporphyrin reduced MOS, corrected mitochondrial dysfunctions, prevented apoptosis and gastric injury. Thus, induction and mitochondrial localization of HO-1 is a novel cytoprotective mechanism against MOS-mediated apoptotic tissue injury. |
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Authors:
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Samik Bindu; Chinmay Pal; Sumanta Dey; Manish Goyal; Athar Alam; Mohd Shameel Iqbal; Shubham Dutta; Souvik Sarkar; Rahul Kumar; Pallab Maity; Uday Bandyopadhyay |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-9 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-12 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Indian Institute of Chemical Biology, India. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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