Redox Regulation of Mitochondrial ATP Synthase: Implications for Cardiac Resynchronization Therapy

Circ Res. 2011 Sep 16;109(7):750-7. doi: 10.1161/CIRCRESAHA.111.246124. Epub 2011 Aug 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiac Resynchronization Therapy*
  • Cysteine
  • Disease Models, Animal
  • Disulfides / metabolism
  • Dogs
  • Glutathione / metabolism
  • HEK293 Cells
  • Heart Failure / enzymology
  • Heart Failure / therapy*
  • 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

Substances

  • Disulfides
  • Oxidative Phosphorylation Coupling Factors
  • F(6) ATPase
  • Mitochondrial Proton-Translocating ATPases
  • Glutathione
  • Cysteine