Redox Regulation of Mitochondrial ATP Synthase Implications for Cardiac Resynchronization Therapy

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 approximate to 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 alpha subunits themselves and between alpha and gamma 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 alpha. 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 alpha subunit in DHF hearts was lower than in CRT hearts (1.53 +/- 0.19-fold, P<0.05). All modifications occurred at ATP synthase alpha subunit Cys294 and Cys to Ser mutation indicated that this residue is critical for ATP synthase function. Conclusions: A selective Cys in ATP synthase alpha subunit is targeted by multiple Ox-PTM suggesting that this Cys residue may act as a redox sensor modulating ATP synthase function. (Circ Res. 2011; 109: 750-757.)