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Bcl-xl regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FoATP synthase

Bcl-xl regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FoATP synthase
Bcl-xl regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FoATP synthase
Anti-apoptotic Bcl2 family proteins such as Bcl-xL protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-xL enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-xLinteracts directly with the ?-subunit of the F1FO ATP synthase, decreasing an ion leak within the F1FO ATPase complex and thereby increasing net transport of H+ by F1FO during F1FO ATPase activity. By patch clamping submitochondrial vesicles enriched in F1FO ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-xL activity increases the membrane leak conductance. In addition, recombinant Bcl-xL protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-xL decreases the level of F1FO enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-xL-expressing neurons.
1465-7392
1224-1233
Alavian, Kambiz N.
f1a40a63-0912-45d6-b343-15ae0d2f6461
Li, Hongmei
dc6391b3-b510-4e46-8b24-dcdca3e73190
Collis, Leon
8a449833-2612-4dd3-92cd-4b9a7435457c
Bonanni, Laura
1ab085f9-525b-4b76-be73-298d1293a09a
Zeng, Lu
e7ae09b7-00d7-4c99-8830-d5c61d286e6a
Sacchetti, Silvio
cf7922bb-84f5-43eb-9219-5ff10ac84f54
Lazrove, Emma
8bdd4fa3-8d76-4b09-86ca-f27189f8cbd2
Nabili, Panah
46a9c728-602c-4a49-a15c-3392f3f2491b
Flaherty, Benjamin
d7eb9b5a-07e6-4fda-b3dc-505c022ea471
Graham, Morven
721dbecb-b610-4082-99ac-dc14d22a9755
Chen, Yingbei
4a277689-a9f1-4153-8896-9bcd5b92d0ea
Messerli, Shanta M.
ac9429aa-1596-46ff-a0b7-12f71704d99f
Mariggio, Maria A.
2013ac77-b262-4f11-b697-05ac12aeee57
Rahner, Christopher
b6862365-45c2-47a3-b0e2-689eb8fb5dc0
McNay, Ewan
464594b5-587f-4833-8134-28243f726c01
Shore, Gordon C.
d7cdd989-7f05-4d35-9351-e7146c9432ff
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Hardwick, J. Marie
7b40cdaf-560d-4df1-84d5-2234cb85c2fa
Jonas, Elizabeth A.
2e88a31d-d1a1-4a9e-8059-71c5143bafe8
Alavian, Kambiz N.
f1a40a63-0912-45d6-b343-15ae0d2f6461
Li, Hongmei
dc6391b3-b510-4e46-8b24-dcdca3e73190
Collis, Leon
8a449833-2612-4dd3-92cd-4b9a7435457c
Bonanni, Laura
1ab085f9-525b-4b76-be73-298d1293a09a
Zeng, Lu
e7ae09b7-00d7-4c99-8830-d5c61d286e6a
Sacchetti, Silvio
cf7922bb-84f5-43eb-9219-5ff10ac84f54
Lazrove, Emma
8bdd4fa3-8d76-4b09-86ca-f27189f8cbd2
Nabili, Panah
46a9c728-602c-4a49-a15c-3392f3f2491b
Flaherty, Benjamin
d7eb9b5a-07e6-4fda-b3dc-505c022ea471
Graham, Morven
721dbecb-b610-4082-99ac-dc14d22a9755
Chen, Yingbei
4a277689-a9f1-4153-8896-9bcd5b92d0ea
Messerli, Shanta M.
ac9429aa-1596-46ff-a0b7-12f71704d99f
Mariggio, Maria A.
2013ac77-b262-4f11-b697-05ac12aeee57
Rahner, Christopher
b6862365-45c2-47a3-b0e2-689eb8fb5dc0
McNay, Ewan
464594b5-587f-4833-8134-28243f726c01
Shore, Gordon C.
d7cdd989-7f05-4d35-9351-e7146c9432ff
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Hardwick, J. Marie
7b40cdaf-560d-4df1-84d5-2234cb85c2fa
Jonas, Elizabeth A.
2e88a31d-d1a1-4a9e-8059-71c5143bafe8

Alavian, Kambiz N., Li, Hongmei, Collis, Leon, Bonanni, Laura, Zeng, Lu, Sacchetti, Silvio, Lazrove, Emma, Nabili, Panah, Flaherty, Benjamin, Graham, Morven, Chen, Yingbei, Messerli, Shanta M., Mariggio, Maria A., Rahner, Christopher, McNay, Ewan, Shore, Gordon C., Smith, Peter J.S., Hardwick, J. Marie and Jonas, Elizabeth A. (2011) Bcl-xl regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FoATP synthase. Nature Cell Biology, 13 (10), 1224-1233. (doi:10.1038/ncb2330). (PMID:21926988)

Record type: Article

Abstract

Anti-apoptotic Bcl2 family proteins such as Bcl-xL protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-xL enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-xLinteracts directly with the ?-subunit of the F1FO ATP synthase, decreasing an ion leak within the F1FO ATPase complex and thereby increasing net transport of H+ by F1FO during F1FO ATPase activity. By patch clamping submitochondrial vesicles enriched in F1FO ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-xL activity increases the membrane leak conductance. In addition, recombinant Bcl-xL protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-xL decreases the level of F1FO enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-xL-expressing neurons.

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e-pub ahead of print date: 18 September 2011
Published date: October 2011
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 195555
URI: https://eprints.soton.ac.uk/id/eprint/195555
ISSN: 1465-7392
PURE UUID: 74f790d2-c20a-416f-a622-ae124096f841
ORCID for Peter J.S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

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Date deposited: 28 Oct 2011 09:26
Last modified: 12 Nov 2019 01:40

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Contributors

Author: Kambiz N. Alavian
Author: Hongmei Li
Author: Leon Collis
Author: Laura Bonanni
Author: Lu Zeng
Author: Silvio Sacchetti
Author: Emma Lazrove
Author: Panah Nabili
Author: Benjamin Flaherty
Author: Morven Graham
Author: Yingbei Chen
Author: Shanta M. Messerli
Author: Maria A. Mariggio
Author: Christopher Rahner
Author: Ewan McNay
Author: Gordon C. Shore
Author: J. Marie Hardwick
Author: Elizabeth A. Jonas

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