The University of Southampton
University of Southampton Institutional Repository

Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency

Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency
Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency
Cellular stress or injury can result in mitochondrial dysfunction, which has been linked to many chronic neurological disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Stressed and dysfunctional mitochondria exhibit an increase in large conductance mitochondrial membrane currents and a decrease in bioenergetic efficiency. Inefficient energy production puts cells, and particularly neurons, at risk of death when energy demands exceed cellular energy production. Here we show that the candidate ALS drug dexpramipexole (DEX; KNS-760704; ((6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) and cyclosporine A (CSA) inhibited increases in ion conductance in whole rat brain-derived mitochondria induced by calcium or treatment with a proteasome inhibitor, although only CSA inhibited calcium-induced permeability transition in liver-derived mitochondria. In several cell lines, including cortical neurons in culture, DEX significantly decreased oxygen consumption while maintaining or increasing production of adenosine triphosphate (ATP). DEX also normalized the metabolic profile of injured cells and was protective against the cytotoxic effects of proteasome inhibition. These data indicate that DEX increases the efficiency of oxidative phosphorylation, possibly by inhibition of a CSA-sensitive mitochondrial conductance.
0006-8993
1-11
Alavian, Kambiz N
7f988785-734d-4405-9888-5ce262020e64
Dworetzky, Steven I
9282c2fd-74f8-4f4b-b5d9-147abd5deed6
Bonanni, Laura
1ab085f9-525b-4b76-be73-298d1293a09a
Zhang, Ping
2def4374-679d-41d1-bf3a-483028a73275
Sacchetti, Silvio
cf7922bb-84f5-43eb-9219-5ff10ac84f54
Mariggio, Maria A
05f3fd5c-5d83-448c-b45d-afedda39605c
Onofrj, Marco
749e4834-6ffe-4307-b790-869b5fc4b3cd
Thomas, Astrid
8c043dfe-811b-4b2d-a65e-123a7685ccfa
Li, Hongmei
dc6391b3-b510-4e46-8b24-dcdca3e73190
Mangold, Jamie E
71e2bce3-ece6-4503-986d-716628581185
Signore, Armando P
caf672cb-a5d4-4181-b156-2ecabd995be5
DeMarco, Ulrike
7833a497-56e3-40fe-a365-d3e925dd268f
Demady, Damon R
23622dfd-9b65-4c36-aa1c-051350de3bfc
Nabili, Panah
46a9c728-602c-4a49-a15c-3392f3f2491b
Lazrove, Emma
8bdd4fa3-8d76-4b09-86ca-f27189f8cbd2
Smith, Peter J S
003de469-9420-4f12-8f0e-8e8d76d28d6c
Gribkoff, Valentin K
1c221639-b075-4a96-80c3-37c8d6f29735
Jonas, Elizabeth A
25aa8e1c-30a1-401b-9afc-f7a919661abc
Alavian, Kambiz N
7f988785-734d-4405-9888-5ce262020e64
Dworetzky, Steven I
9282c2fd-74f8-4f4b-b5d9-147abd5deed6
Bonanni, Laura
1ab085f9-525b-4b76-be73-298d1293a09a
Zhang, Ping
2def4374-679d-41d1-bf3a-483028a73275
Sacchetti, Silvio
cf7922bb-84f5-43eb-9219-5ff10ac84f54
Mariggio, Maria A
05f3fd5c-5d83-448c-b45d-afedda39605c
Onofrj, Marco
749e4834-6ffe-4307-b790-869b5fc4b3cd
Thomas, Astrid
8c043dfe-811b-4b2d-a65e-123a7685ccfa
Li, Hongmei
dc6391b3-b510-4e46-8b24-dcdca3e73190
Mangold, Jamie E
71e2bce3-ece6-4503-986d-716628581185
Signore, Armando P
caf672cb-a5d4-4181-b156-2ecabd995be5
DeMarco, Ulrike
7833a497-56e3-40fe-a365-d3e925dd268f
Demady, Damon R
23622dfd-9b65-4c36-aa1c-051350de3bfc
Nabili, Panah
46a9c728-602c-4a49-a15c-3392f3f2491b
Lazrove, Emma
8bdd4fa3-8d76-4b09-86ca-f27189f8cbd2
Smith, Peter J S
003de469-9420-4f12-8f0e-8e8d76d28d6c
Gribkoff, Valentin K
1c221639-b075-4a96-80c3-37c8d6f29735
Jonas, Elizabeth A
25aa8e1c-30a1-401b-9afc-f7a919661abc

Alavian, Kambiz N, Dworetzky, Steven I, Bonanni, Laura, Zhang, Ping, Sacchetti, Silvio, Mariggio, Maria A, Onofrj, Marco, Thomas, Astrid, Li, Hongmei, Mangold, Jamie E, Signore, Armando P, DeMarco, Ulrike, Demady, Damon R, Nabili, Panah, Lazrove, Emma, Smith, Peter J S, Gribkoff, Valentin K and Jonas, Elizabeth A (2012) Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency. Brain Research, 1446, 1-11.

Record type: Article

Abstract

Cellular stress or injury can result in mitochondrial dysfunction, which has been linked to many chronic neurological disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Stressed and dysfunctional mitochondria exhibit an increase in large conductance mitochondrial membrane currents and a decrease in bioenergetic efficiency. Inefficient energy production puts cells, and particularly neurons, at risk of death when energy demands exceed cellular energy production. Here we show that the candidate ALS drug dexpramipexole (DEX; KNS-760704; ((6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) and cyclosporine A (CSA) inhibited increases in ion conductance in whole rat brain-derived mitochondria induced by calcium or treatment with a proteasome inhibitor, although only CSA inhibited calcium-induced permeability transition in liver-derived mitochondria. In several cell lines, including cortical neurons in culture, DEX significantly decreased oxygen consumption while maintaining or increasing production of adenosine triphosphate (ATP). DEX also normalized the metabolic profile of injured cells and was protective against the cytotoxic effects of proteasome inhibition. These data indicate that DEX increases the efficiency of oxidative phosphorylation, possibly by inhibition of a CSA-sensitive mitochondrial conductance.

Full text not available from this repository.

More information

Accepted/In Press date: 28 January 2012
Published date: 29 March 2012
Organisations: Faculty of Natural and Environmental Sciences

Identifiers

Local EPrints ID: 334084
URI: https://eprints.soton.ac.uk/id/eprint/334084
ISSN: 0006-8993
PURE UUID: 3e5c3980-6c68-4bbe-bf34-12545cf5247f
ORCID for Peter J S Smith: ORCID iD orcid.org/0000-0003-4400-6853

Catalogue record

Date deposited: 06 Mar 2012 09:44
Last modified: 06 Jun 2018 12:31

Export record

Contributors

Author: Kambiz N Alavian
Author: Steven I Dworetzky
Author: Laura Bonanni
Author: Ping Zhang
Author: Silvio Sacchetti
Author: Maria A Mariggio
Author: Marco Onofrj
Author: Astrid Thomas
Author: Hongmei Li
Author: Jamie E Mangold
Author: Armando P Signore
Author: Ulrike DeMarco
Author: Damon R Demady
Author: Panah Nabili
Author: Emma Lazrove
Author: Peter J S Smith ORCID iD
Author: Valentin K Gribkoff
Author: Elizabeth A Jonas

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×