Redox regulation of mitochondrial ATP synthase: implications for cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) is an effective clinical treatment for heart failure patients with conduction delay, impaired contraction, and energetics. Our recent studies have revealed that mitochondrial posttranslational modifications (PTM) may contribute to its benefits, motivating the...

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Vydáno v:Circulation research Ročník 109; číslo 7; s. 750
Hlavní autoři: Wang, Sheng-Bing, Foster, D Brian, Rucker, Jasma, O'Rourke, Brian, Kass, David A, Van Eyk, Jennifer E
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 16.09.2011
Témata:
Animals
Cardiac Resynchronization Therapy
Cysteine
Disease Models, Animal
Disulfides - metabolism
Dogs
Glutathione - metabolism
Heart Failure - enzymology
Heart Failure - therapy
HEK293 Cells
Humans
Mitochondria, Heart - enzymology
Mitochondrial Proton-Translocating ATPases - genetics
Mitochondrial Proton-Translocating ATPases - metabolism
Mutation
Myocardium - enzymology
Nitrosation
Oxidation-Reduction
Oxidative Phosphorylation Coupling Factors - metabolism
Protein Processing, Post-Translational
RNA Interference
Transfection
ISSN:1524-4571, 1524-4571
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Shrnutí:Cardiac resynchronization therapy (CRT) is an effective clinical treatment for heart failure patients with conduction delay, impaired contraction, and energetics. Our recent studies have revealed that mitochondrial posttranslational modifications (PTM) may contribute to its benefits, motivating the present study of the oxidative regulation of mitochondrial ATP synthase. We tested whether CRT alteration of ATP synthase function is linked to cysteine (Cys) oxidative PTM (Ox-PTM) of specific ATP synthase subunits. Canine left ventricular myocardium was collected under conditions to preserve Ox-PTM from control, dyssynchronous heart failure (DHF), or hearts that had undergone CRT. In-gel ATPase activity showed that CRT increased ATPase activity by approximately 2-fold (P<0.05) over DHF, approaching control levels, and this effect was recapitulated with a reducing agent. ATP synthase function and 3 Ox-PTM: disulfide bond, S-glutathionylation and S-nitrosation were assessed. ATP synthase from DHF hearts contained 2 novel disulfide bonds, between ATP synthase α subunits themselves and between α and γ subunits, both of which were decreased in CRT hearts (4.38 ± 0.13- and 4.23 ± 0.36-fold, respectively, P<0.01). S-glutathionylation of ATP synthase α subunit occurred in DHF hearts and was decreased by CRT (1.56 ± 0.16-fold, P<0.04). In contrast, S-nitrosation of ATP synthase α subunit in DHF hearts was lower than in CRT hearts (1.53 ± 0.19-fold, P<0.05). All modifications occurred at ATP synthase α subunit Cys294 and Cys to Ser mutation indicated that this residue is critical for ATP synthase function. A selective Cys in ATP synthase α subunit is targeted by multiple Ox-PTM suggesting that this Cys residue may act as a redox sensor modulating ATP synthase function.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1524-4571
1524-4571
DOI:10.1161/CIRCRESAHA.111.246124