Document Detail

Bnip3 functions as a mitochondrial sensor of oxidative stress during myocardial ischemia and reperfusion.
MedLine Citation:
PMID:  18790835     Owner:  NLM     Status:  MEDLINE    
Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) is a member of the Bcl-2 homology domain 3-only subfamily of proapoptotic Bcl-2 proteins and is associated with cell death in the myocardium. In this study, we investigated the potential mechanism(s) by which Bnip3 activity is regulated. We found that Bnip3 forms a DTT-sensitive homodimer that increased after myocardial ischemia-reperfusion (I/R). The presence of the antioxidant N-acetylcysteine reduced I/R-induced homodimerization of Bnip3. Overexpression of Bnip3 in cells revealed that most of exogenous Bnip3 exists as a DTT-sensitive homodimer that correlated with increased cell death. In contrast, endogenous Bnip3 existed mainly as a monomer under normal conditions in the heart. Screening of the Bnip3 protein sequence revealed a single conserved cysteine residue at position 64. Mutation of this cysteine to alanine (Bnip3C64A) or deletion of the NH2-terminus (amino acids 1-64) resulted in reduced cell death activity of Bnip3. Moreover, mutation of a histidine residue in the COOH-terminal transmembrane domain to alanine (Bnip3H173A) almost completely inhibited the cell death activity of Bnip3. Bnip3C64A had a reduced ability to interact with Bnip3, whereas Bnip3H173A was completely unable to interact with Bnip3, suggesting that homodimerization is important for Bnip3 function. A consequence of I/R is the production of reactive oxygen species and oxidation of proteins, which promotes the formation of disulfide bonds between proteins. Thus, these experiments suggest that Bnip3 functions as a redox sensor where increased oxidative stress induces homodimerization and activation of Bnip3 via cooperation of the NH2-terminal cysteine residue and the COOH-terminal transmembrane domain.
Dieter A Kubli; Melissa N Quinsay; Chengqun Huang; Youngil Lee; Asa B Gustafsson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-09-12
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  295     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-10     Completed Date:  2008-12-22     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H2025-31     Citation Subset:  IM    
BioScience Center, San Diego State University, 5500 Campanile Dr., San Diego, CA 92182-4650, USA.
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MeSH Terms
Disease Models, Animal
HeLa Cells
Membrane Proteins / chemistry,  genetics,  metabolism*
Mitochondria, Heart / metabolism*,  pathology
Myocardial Reperfusion Injury / metabolism*,  pathology
Myocytes, Cardiac / metabolism*,  pathology
Oxidative Stress*
Protein Multimerization
Protein Structure, Tertiary
Proto-Oncogene Proteins / chemistry,  genetics,  metabolism*
Rats, Sprague-Dawley
Reactive Oxygen Species / metabolism
Recombinant Fusion Proteins / metabolism
Grant Support
Reg. No./Substance:
0/BNIP3 protein, rat; 0/Membrane Proteins; 0/Proto-Oncogene Proteins; 0/Reactive Oxygen Species; 0/Recombinant Fusion Proteins; 52-90-4/Cysteine

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