Imperial College London
Alternate

Dr Kambiz N. Alavian, PhD, SFHEA, FLS, FRSB

Faculty of Medicine, Department of Brain Sciences

Reader in Neuroscience
 
 
 
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Contact

 

+44 (0)20 7594 7006k.alavian Website

 
 
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Assistant

 

Mrs Hadeel Abdeen +44 (0)20 7594 7014

 
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Location

 

E507Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Alavian:2014:10.1073/pnas.1401591111,
author = {Alavian, KN and Beutner, G and Lazrove, E and Sacchetti, S and Park, H-A and Licznerski, P and Li, H and Nabili, P and Hockensmith, K and Graham, M and Porter, GA and Jonas, EA},
doi = {10.1073/pnas.1401591111},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
pages = {10580--10585},
title = {An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore},
url = {http://dx.doi.org/10.1073/pnas.1401591111},
volume = {111},
year = {2014}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cellular calcium (Ca2+) dysregulation followed by rapid loss of IMM potential known as permeability transition (PT), which produces osmotic shifts, metabolic dysfunction, and cell death. The molecular identity of the mitochondrial PT pore (mPTP) was previously unknown. We show that the purified reconstituted c-subunit ring of the FO of the F1FO ATP synthase forms a voltage-sensitive channel, the persistent opening of which leads to rapid and uncontrolled depolarization of the IMM in cells. Prolonged high matrix Ca2+ enlarges the c-subunit ring and unhooks it from cyclophilin D/cyclosporine A binding sites in the ATP synthase F1, providing a mechanism for mPTP opening. In contrast, recombinant F1 beta-subunit applied exogenously to the purified c-subunit enhances the probability of pore closure. Depletion of the c-subunit attenuates Ca2+-induced IMM depolarization and inhibits Ca2+ and reactive oxygen species-induced cell death whereas increasing the expression or single-channel conductance of the c-subunit sensitizes to death. We conclude that a highly regulated c-subunit leak channel is a candidate for the mPTP. Beyond cell death, these findings also imply that increasing the probability of c-subunit channel closure in a healthy cell will enhance IMM coupling and increase cellular metabolic efficiency.
AU  - Alavian,KN
AU  - Beutner,G
AU  - Lazrove,E
AU  - Sacchetti,S
AU  - Park,H-A
AU  - Licznerski,P
AU  - Li,H
AU  - Nabili,P
AU  - Hockensmith,K
AU  - Graham,M
AU  - Porter,GA
AU  - Jonas,EA
DO  - 10.1073/pnas.1401591111
EP  - 10585
PY  - 2014///
SN  - 0027-8424
SP  - 10580
TI  - An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore
T2  - Proceedings of the National Academy of Sciences of the United States of America
UR  - http://dx.doi.org/10.1073/pnas.1401591111
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000339310700049&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.pnas.org/content/111/29/10580
VL  - 111
ER  -
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