Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex

Valentina Giorgio, Elena Bisetto, Maria Eugenia Soriano, Federica Dabbeni-Sala, Emy Basso, Valeria Petronilli, Michael A. Forte, Paolo Bernardi, Giovanna Lippe

Research output: Contribution to journalArticle

186 Scopus citations

Abstract

Blue native gel electrophoresis purification and immunoprecipitation of F0F1-ATP synthase from bovine heart mitochondria revealed that cyclophilin (CyP) D associates to the complex. Treatment of intact mitochondria with the membrane-permeable bifunctional reagent dimethyl 3,3-dithiobis-propionimidate (DTBP) cross-linked CyPD with the lateral stalk of ATP synthase, whereas no interactions with F1 sector subunits, the ATP synthase natural inhibitor protein IF1, and the ATP/ADP carrier were observed. The ATP synthase-CyPD interactions have functional consequences on enzyme catalysis and are modulated by phosphate (increased CyPD binding and decreased enzyme activity) and cyclosporin (Cs) A (decreased CyPD binding and increased enzyme activity). Treatment of MgATP submitochondrial particles or intact mitochondria with CsA displaced CyPD from membranes and activated both hydrolysis and synthesis of ATP sustained by the enzyme. No effect of CsA was detected in CyPD-null mitochondria, which displayed a higher specific activity of the ATP synthase than wild-type mitochondria. Modulation by CyPD binding appears to be independent of IF1, whose association to ATP synthase was not affected by CsA treatment. These findings demonstrate that CyPD association to the lateral stalk of ATP synthase modulates the activity of the complex.

Original languageEnglish (US)
Pages (from-to)33982-33988
Number of pages7
JournalJournal of Biological Chemistry
Volume284
Issue number49
DOIs
StatePublished - Dec 4 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Giorgio, V., Bisetto, E., Soriano, M. E., Dabbeni-Sala, F., Basso, E., Petronilli, V., Forte, M. A., Bernardi, P., & Lippe, G. (2009). Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex. Journal of Biological Chemistry, 284(49), 33982-33988. https://doi.org/10.1074/jbc.M109.020115