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The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole

The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole
The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole
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.
0026-895X
1-8
Alavian, K.N.
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Dworetzky, S.I.
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Bonanni, L.
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Zhang, P.
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Sacchetti, S.
53893999-b251-4bc8-8d20-2577b3815bc6
Li, H.
e6f231b5-28cd-425f-b136-55ceab5d00db
Signore, A.P.
f87cc9d2-16ff-4276-ba2d-3691015a88ba
Smith, P.J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Gribkoff, V.K.
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Jonas, E.A.
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Alavian, K.N.
3b376094-6c06-4cc5-b6af-8fa28f25c8c7
Dworetzky, S.I.
495e760f-fcd2-4031-ba9e-9182fc9877c2
Bonanni, L.
1b333334-58db-4dbd-8e1f-8da60f097f84
Zhang, P.
58020138-8fa1-4555-b886-32df14964cfa
Sacchetti, S.
53893999-b251-4bc8-8d20-2577b3815bc6
Li, H.
e6f231b5-28cd-425f-b136-55ceab5d00db
Signore, A.P.
f87cc9d2-16ff-4276-ba2d-3691015a88ba
Smith, P.J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Gribkoff, V.K.
5fad65d4-86f1-4811-a93f-9b60dbb785a9
Jonas, E.A.
4bab5222-aa7b-4d4d-93b4-45c60e614a8a

Alavian, K.N., Dworetzky, S.I., Bonanni, L., Zhang, P., Sacchetti, S., Li, H., Signore, A.P., Smith, P.J.S., Gribkoff, V.K. and Jonas, E.A. (2015) The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole. Molecular Pharmacology, 87 (1), 1-8. (doi:10.1124/mol.114.095661). (PMID:25332381)

Record type: Article

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.

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More information

Accepted/In Press date: 20 October 2014
Published date: January 2015
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 393266
URI: http://eprints.soton.ac.uk/id/eprint/393266
ISSN: 0026-895X
PURE UUID: a0216e1f-a0b9-448e-9509-18ebaf8771f9
ORCID for P.J.S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

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Date deposited: 25 Apr 2016 11:10
Last modified: 15 Aug 2019 00:38

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