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Research ArticleArticle

The Mitochondrial Complex V–Associated Large-Conductance Inner Membrane Current Is Regulated by Cyclosporine and Dexpramipexole

Kambiz N. Alavian, Steven I. Dworetzky, Laura Bonanni, Ping Zhang, Silvio Sacchetti, Hongmei Li, Armando P. Signore, Peter J. S. Smith, Valentin K. Gribkoff and Elizabeth A. Jonas
Molecular Pharmacology January 2015, 87 (1) 1-8; DOI: https://doi.org/10.1124/mol.114.095661
Kambiz N. Alavian
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Steven I. Dworetzky
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Laura Bonanni
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Ping Zhang
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Silvio Sacchetti
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Hongmei Li
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Armando P. Signore
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Peter J. S. Smith
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Valentin K. Gribkoff
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Elizabeth A. Jonas
Department of Internal Medicine (K.N.A., P.Z., S.S., H.L., E.A.J.) and Department of Neurobiology (E.A.J.), Yale University School of Medicine, New Haven, Connecticut; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom (K.N.A.); Department of Neuroscience, Imaging and Clinical Sciences, University G.d’Annunzio of Chieti-Pescara, Chieti-Pescara, Italy (L.B.); Knopp Biosciences LLC, Pittsburgh, Pennsylvania (S.I.D., A.P.S., V.K.G.); and Biocurrents Research Center, Marine Biological Laboratory, Woods Hole, Massachusetts (P.J.S.S.)
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Abstract

Inefficiency of oxidative phosphorylation can result from futile leak conductance through the inner mitochondrial membrane. Stress or injury may exacerbate this leak conductance, putting cells, and particularly neurons, at risk of dysfunction and even death when energy demand exceeds cellular energy production. Using a novel method, we have recently described an ion conductance consistent with mitochondrial permeability transition pore (mPTP) within the c-subunit of the ATP synthase. Excitotoxicity, reactive oxygen species–producing stimuli, or elevated mitochondrial matrix calcium opens the channel, which is inhibited by cyclosporine A and ATP/ADP. Here we show that ATP and the neuroprotective drug dexpramipexole (DEX) inhibited an ion conductance consistent with this c-subunit channel (mPTP) in brain-derived submitochondrial vesicles (SMVs) enriched for F1FO ATP synthase (complex V). Treatment of SMVs with urea denatured extramembrane components of complex V, eliminated DEX- but not ATP-mediated current inhibition, and reduced binding of [14C]DEX. Direct effects of DEX on the synthesis and hydrolysis of ATP by complex V suggest that interaction of the compound with its target results in functional conformational changes in the enzyme complex. [14C]DEX bound specifically to purified recombinant b and oligomycin sensitivity–conferring protein subunits of the mitochondrial F1FO ATP synthase. Previous data indicate that DEX increased the efficiency of energy production in cells, including neurons. Taken together, these studies suggest that modulation of a complex V–associated inner mitochondrial membrane current is metabolically important and may represent an avenue for the development of new therapeutics for neurodegenerative disorders.

Footnotes

    • Received August 29, 2014.
    • Accepted October 20, 2014.
  • This work was supported by a grant from Knopp Biosciences LLC to Yale University School of Medicine, by the National Institutes of Health [Grants R01-NS045876 and R01-NS064967], and by the Italian Ministry of Health [Young Researchers Grant 2007 (Dementia with Lewy Bodies: New Diagnostic Markers and Therapeutic Implications)].

  • dx.doi.org/10.1124/mol.114.095661.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (1)
Molecular Pharmacology
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1 Jan 2015
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Research ArticleArticle

Mitochondrial Complex V–Associated Uncoupling Current

Kambiz N. Alavian, Steven I. Dworetzky, Laura Bonanni, Ping Zhang, Silvio Sacchetti, Hongmei Li, Armando P. Signore, Peter J. S. Smith, Valentin K. Gribkoff and Elizabeth A. Jonas
Molecular Pharmacology January 1, 2015, 87 (1) 1-8; DOI: https://doi.org/10.1124/mol.114.095661

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Research ArticleArticle

Mitochondrial Complex V–Associated Uncoupling Current

Kambiz N. Alavian, Steven I. Dworetzky, Laura Bonanni, Ping Zhang, Silvio Sacchetti, Hongmei Li, Armando P. Signore, Peter J. S. Smith, Valentin K. Gribkoff and Elizabeth A. Jonas
Molecular Pharmacology January 1, 2015, 87 (1) 1-8; DOI: https://doi.org/10.1124/mol.114.095661
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