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Mechanism of inhibition of mitochondrial ATP synthase by 17β-Estradiol.
MedLine Citation:
PMID:  23274738     Owner:  NLM     Status:  Publisher    
17β-estradiol (E2) is considered to modulate the ATP synthase activity through direct binding to the oligomycin sensitive-conferring protein. We have previously demonstrated that E2 increases the amplitude of depolarization associated with the addition of ADP to energized mitochondria (i.e., to initiate a phosphorylative cycle) suggesting a direct action on the phosphorylative system of mitochondria. The purpose of the present study was to investigate the underlying mechanisms responsible for this effect. We show here that E2 modulates the activity of mitochondrial ATP synthase by promoting the intrinsic uncoupling ("slipping") of the ATP synthase. E2 depressed RCR, ADP/O ratio and state 3 respiration, whereas state 4 respiration was increased and V(FCCP) (uncoupled respiration) remained unaltered. In contrast to the stimulatory effect on state 4 respiration, state 2 respiration and V(olig) were not affected by E2. The effect of E2 appeared to be directed towards ATP synthase, since glutamate/malate respiration, uncoupled from the electron transport chain, was unaffected by E2. Apparently, E2 allows a proton back-leak through the F(o) component of ATP synthase. This action of E2 is dependent on the presence of ATP, is more pronounced at high membrane potentials, and it is reversed by oligomycin (a Fo-ATP synthase inhibitor) but not by resveratrol (a F(1)-ATP synthase inhibitor). Altogether, our data provide a mechanistic explanation for the effect of E2 at the level of mitochondrial ATP synthase.
António J M Moreno; Paula I Moreira; José B A Custódio; Maria S Santos
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-29
Journal Detail:
Title:  Journal of bioenergetics and biomembranes     Volume:  -     ISSN:  1573-6881     ISO Abbreviation:  J. Bioenerg. Biomembr.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-31     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7701859     Medline TA:  J Bioenerg Biomembr     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Life Sciences - Faculty of Sciences and Technology, Institute of Marine Research, University of Coimbra, Apartado 3046, 3001-401, Coimbra, Portugal,
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