The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole.
Identifieur interne : 000268 ( Main/Exploration ); précédent : 000267; suivant : 000269The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole.
Auteurs : Kambiz N. Alavian ; Steven I. Dworetzky ; Laura Bonanni ; Ping Zhang ; Silvio Sacchetti ; Hongmei Li ; Armando P. Signore ; Peter J S. Smith ; Valentin K. Gribkoff ; Elizabeth A. Jonas [États-Unis]Source :
- Molecular pharmacology [ 1521-0111 ] ; 2015.
Descripteurs français
- KwdFr :
- Adénosine triphosphate (métabolisme), Adénosine triphosphate (pharmacologie), Benzothiazoles (pharmacologie), Ciclosporine (pharmacologie), Encéphale (cytologie), Encéphale (enzymologie), Humains, Membranes mitochondriales (), Proton-Translocating ATPases (métabolisme), Protéines de transport de la membrane mitochondriale (métabolisme).
- MESH :
- cytologie : Encéphale.
- enzymologie : Encéphale.
- métabolisme : Adénosine triphosphate, Proton-Translocating ATPases, Protéines de transport de la membrane mitochondriale.
- pharmacologie : Adénosine triphosphate, Benzothiazoles, Ciclosporine.
- Humains, Membranes mitochondriales.
English descriptors
- KwdEn :
- Adenosine Triphosphate (metabolism), Adenosine Triphosphate (pharmacology), Benzothiazoles (pharmacology), Brain (cytology), Brain (enzymology), Cyclosporine (pharmacology), Humans, Mitochondrial Membrane Transport Proteins (metabolism), Mitochondrial Membranes (drug effects), Proton-Translocating ATPases (metabolism).
- MESH :
- chemical , metabolism : Adenosine Triphosphate, Mitochondrial Membrane Transport Proteins, Proton-Translocating ATPases.
- chemical , pharmacology : Adenosine Triphosphate, Benzothiazoles, Cyclosporine.
- cytology : Brain.
- drug effects : Mitochondrial Membranes.
- enzymology : Brain.
- Humans.
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 [(14)C]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. [(14)C]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.
DOI: 10.1124/mol.114.095661
PubMed: 25332381
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole.</title><author><name sortKey="Alavian, Kambiz N" sort="Alavian, Kambiz N" uniqKey="Alavian K" first="Kambiz N" last="Alavian">Kambiz N. Alavian</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Dworetzky, Steven I" sort="Dworetzky, Steven I" uniqKey="Dworetzky S" first="Steven I" last="Dworetzky">Steven I. Dworetzky</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Bonanni, Laura" sort="Bonanni, Laura" uniqKey="Bonanni L" first="Laura" last="Bonanni">Laura Bonanni</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Zhang, Ping" sort="Zhang, Ping" uniqKey="Zhang P" first="Ping" last="Zhang">Ping Zhang</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Sacchetti, Silvio" sort="Sacchetti, Silvio" uniqKey="Sacchetti S" first="Silvio" last="Sacchetti">Silvio Sacchetti</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Li, Hongmei" sort="Li, Hongmei" uniqKey="Li H" first="Hongmei" last="Li">Hongmei Li</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Signore, Armando P" sort="Signore, Armando P" uniqKey="Signore A" first="Armando P" last="Signore">Armando P. Signore</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Smith, Peter J S" sort="Smith, Peter J S" uniqKey="Smith P" first="Peter J S" last="Smith">Peter J S. Smith</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Gribkoff, Valentin K" sort="Gribkoff, Valentin K" uniqKey="Gribkoff V" first="Valentin K" last="Gribkoff">Valentin K. Gribkoff</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Jonas, Elizabeth A" sort="Jonas, Elizabeth A" uniqKey="Jonas E" first="Elizabeth A" last="Jonas">Elizabeth A. Jonas</name><affiliation wicri:level="1"><nlm:affiliation>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.) Elizabeth.jonas@yale.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:25332381</idno><idno type="pmid">25332381</idno><idno type="doi">10.1124/mol.114.095661</idno><idno type="wicri:Area/PubMed/Corpus">000A41</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000A41</idno><idno type="wicri:Area/PubMed/Curation">000A41</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000A41</idno><idno type="wicri:Area/PubMed/Checkpoint">000A41</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000A41</idno><idno type="wicri:Area/Ncbi/Merge">003B28</idno><idno type="wicri:Area/Ncbi/Curation">003B28</idno><idno type="wicri:Area/Ncbi/Checkpoint">003B28</idno><idno type="wicri:Area/Main/Merge">000268</idno><idno type="wicri:Area/Main/Curation">000268</idno><idno type="wicri:Area/Main/Exploration">000268</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole.</title><author><name sortKey="Alavian, Kambiz N" sort="Alavian, Kambiz N" uniqKey="Alavian K" first="Kambiz N" last="Alavian">Kambiz N. Alavian</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Dworetzky, Steven I" sort="Dworetzky, Steven I" uniqKey="Dworetzky S" first="Steven I" last="Dworetzky">Steven I. Dworetzky</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Bonanni, Laura" sort="Bonanni, Laura" uniqKey="Bonanni L" first="Laura" last="Bonanni">Laura Bonanni</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Zhang, Ping" sort="Zhang, Ping" uniqKey="Zhang P" first="Ping" last="Zhang">Ping Zhang</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Sacchetti, Silvio" sort="Sacchetti, Silvio" uniqKey="Sacchetti S" first="Silvio" last="Sacchetti">Silvio Sacchetti</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Li, Hongmei" sort="Li, Hongmei" uniqKey="Li H" first="Hongmei" last="Li">Hongmei Li</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Signore, Armando P" sort="Signore, Armando P" uniqKey="Signore A" first="Armando P" last="Signore">Armando P. Signore</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Smith, Peter J S" sort="Smith, Peter J S" uniqKey="Smith P" first="Peter J S" last="Smith">Peter J S. Smith</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Gribkoff, Valentin K" sort="Gribkoff, Valentin K" uniqKey="Gribkoff V" first="Valentin K" last="Gribkoff">Valentin K. Gribkoff</name><affiliation><nlm:affiliation>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.).</nlm:affiliation><wicri:noCountry code="subField">Massachusetts (P.J.S.S.).</wicri:noCountry></affiliation></author><author><name sortKey="Jonas, Elizabeth A" sort="Jonas, Elizabeth A" uniqKey="Jonas E" first="Elizabeth A" last="Jonas">Elizabeth A. Jonas</name><affiliation wicri:level="1"><nlm:affiliation>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.) Elizabeth.jonas@yale.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><series><title level="j">Molecular pharmacology</title><idno type="eISSN">1521-0111</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenosine Triphosphate (metabolism)</term><term>Adenosine Triphosphate (pharmacology)</term><term>Benzothiazoles (pharmacology)</term><term>Brain (cytology)</term><term>Brain (enzymology)</term><term>Cyclosporine (pharmacology)</term><term>Humans</term><term>Mitochondrial Membrane Transport Proteins (metabolism)</term><term>Mitochondrial Membranes (drug effects)</term><term>Proton-Translocating ATPases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adénosine triphosphate (métabolisme)</term><term>Adénosine triphosphate (pharmacologie)</term><term>Benzothiazoles (pharmacologie)</term><term>Ciclosporine (pharmacologie)</term><term>Encéphale (cytologie)</term><term>Encéphale (enzymologie)</term><term>Humains</term><term>Membranes mitochondriales ()</term><term>Proton-Translocating ATPases (métabolisme)</term><term>Protéines de transport de la membrane mitochondriale (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adenosine Triphosphate</term><term>Mitochondrial Membrane Transport Proteins</term><term>Proton-Translocating ATPases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Adenosine Triphosphate</term><term>Benzothiazoles</term><term>Cyclosporine</term></keywords><keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Encéphale</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Brain</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Mitochondrial Membranes</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Encéphale</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Brain</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Adénosine triphosphate</term><term>Proton-Translocating ATPases</term><term>Protéines de transport de la membrane mitochondriale</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Adénosine triphosphate</term><term>Benzothiazoles</term><term>Ciclosporine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Membranes mitochondriales</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 [(14)C]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. [(14)C]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.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Alavian, Kambiz N" sort="Alavian, Kambiz N" uniqKey="Alavian K" first="Kambiz N" last="Alavian">Kambiz N. Alavian</name><name sortKey="Bonanni, Laura" sort="Bonanni, Laura" uniqKey="Bonanni L" first="Laura" last="Bonanni">Laura Bonanni</name><name sortKey="Dworetzky, Steven I" sort="Dworetzky, Steven I" uniqKey="Dworetzky S" first="Steven I" last="Dworetzky">Steven I. Dworetzky</name><name sortKey="Gribkoff, Valentin K" sort="Gribkoff, Valentin K" uniqKey="Gribkoff V" first="Valentin K" last="Gribkoff">Valentin K. Gribkoff</name><name sortKey="Li, Hongmei" sort="Li, Hongmei" uniqKey="Li H" first="Hongmei" last="Li">Hongmei Li</name><name sortKey="Sacchetti, Silvio" sort="Sacchetti, Silvio" uniqKey="Sacchetti S" first="Silvio" last="Sacchetti">Silvio Sacchetti</name><name sortKey="Signore, Armando P" sort="Signore, Armando P" uniqKey="Signore A" first="Armando P" last="Signore">Armando P. Signore</name><name sortKey="Smith, Peter J S" sort="Smith, Peter J S" uniqKey="Smith P" first="Peter J S" last="Smith">Peter J S. Smith</name><name sortKey="Zhang, Ping" sort="Zhang, Ping" uniqKey="Zhang P" first="Ping" last="Zhang">Ping Zhang</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Jonas, Elizabeth A" sort="Jonas, Elizabeth A" uniqKey="Jonas E" first="Elizabeth A" last="Jonas">Elizabeth A. Jonas</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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