title: 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.
abstract: The mechanism of action of heme oxygenase-1 (HO-1) in mitochondrial oxidative stress (MOS)-mediated apoptotic tissue injury was investigated. MOS-mediated gastric mucosal apoptosis and injury were introduced in rat by indomethacin, a non-steroidal anti-inflammatory drug. Here, we report that HO-1 was not only induced but also translocated to mitochondria during gastric mucosal injury to favor repair mechanisms. Furthermore, mitochondrial translocation of HO-1 resulted in the prevention of MOS and mitochondrial pathology as evident from the restoration of the complex I-driven mitochondrial respiratory control ratio and transmembrane potential. Mitochondrial translocation of HO-1 also resulted 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, was increased inside mitochondria during gastric injury, and mitochondrial entry of HO-1 decreased intramitochondrial free heme content, suggesting that a purpose of mitochondrial translocation of HO-1 is to detoxify accumulated heme. Heme may activate nuclear translocation of NF-E2-related factor 2 to induce HO-1 through reactive oxygen species generation. Electrophoretic mobility shift assay and chromatin immunoprecipitation studies indicated nuclear translocation of NF-E2-related factor 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 the respiratory control ratio and transmembrane potential and enhanced MOS and apoptosis. In contrast, induction of HO-1 by cobalt protoporphyrin reduced MOS, corrected mitochondrial dysfunctions, and prevented apoptosis and gastric injury. Thus, induction and mitochondrial localization of HO-1 are a novel cytoprotective mechanism against MOS-mediated apoptotic tissue injury.
authors: Department of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors: Samik
authors: S
authors: Bindu
authors: Chinmay
authors: C
authors: Pal
authors: Sumanta
authors: S
authors: Dey
authors: Manish
authors: M
authors: Goyal
authors: Athar
authors: A
authors: Alam
authors: Mohd Shameel
authors: MS
authors: Iqbal
authors: Shubham
authors: S
authors: Dutta
authors: Souvik
authors: S
authors: Sarkar
authors: Rahul
authors: R
authors: Kumar
authors: Pallab
authors: P
authors: Maity
authors: Uday
authors: U
authors: Bandyopadhyay
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D005753:Gastric Mucosa / Q000201:enzymology* / Q000293:injuries*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000201:enzymology*; D050983:NF-E2 Transcription Factor / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D050983:NF-E2 Transcription Factor; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D007213:Indomethacin