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

Abstract：

RATIONALE: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. OBJECTIVES:We tested whether CRT alteration of ATP synthase function is linked to cysteine (Cys) oxidative PTM (Ox-PTM) of specific ATP synthase subunits. METHODS AND RESULTS: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. CONCLUSIONS: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.

journal_name

Circ Res

journal_title

Circulation research

authors

Wang SB,Foster DB,Rucker J,O'Rourke B,Kass DA,Van Eyk JE

doi

10.1161/CIRCRESAHA.111.246124

subject

Has Abstract

pub_date

2011-09-16 00:00:00

pages

750-7

issue

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.111.246124

journal_volume

109

pub_type

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