Imperial College London

ProfessorDavidCarling

Faculty of MedicineInstitute of Clinical Sciences

Professor of Biochemistry
 
 
 
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Contact

 

+44 (0)20 3313 4313david.carling

 
 
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Location

 

3rd Fl CRBHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hinchy:2018:10.1074/jbc.RA118.002579,
author = {Hinchy, EC and Gruszczyk, AV and Willows, R and Navaratnam, N and Hall, AR and Bates, G and Bright, TP and Krieg, T and Carling, D and Murphy, MP},
doi = {10.1074/jbc.RA118.002579},
journal = {JOURNAL OF BIOLOGICAL CHEMISTRY},
pages = {17208--17217},
title = {Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly},
url = {http://dx.doi.org/10.1074/jbc.RA118.002579},
volume = {293},
year = {2018}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Mitochondrial reactive oxygen species (ROS) production is a tightly regulated redox signal that transmits information from the organelle to the cell. Other mitochondrial signals, such as ATP, are sensed by enzymes, including the key metabolic sensor and regulator, AMP-activated protein kinase (AMPK). AMPK responds to the cellular ATP/AMP and ATP/ADP ratios by matching mitochondrial ATP production to demand. Previous reports proposed that AMPK activity also responds to ROS, by ROS acting on redox-sensitive cysteine residues (Cys-299/Cys-304) on the AMPK α subunit. This suggests an appealing model in which mitochondria fine-tune AMPK activity by both adenine nucleotide–dependent mechanisms and by redox signals. Here we assessed whether physiological levels of ROS directly alter AMPK activity. To this end we added exogenous hydrogen peroxide (H2O2) to cells and utilized the mitochondria-targeted redox cycler MitoParaquat to generate ROS within mitochondria without disrupting oxidative phosphorylation. Mitochondrial and cytosolic thiol oxidation was assessed by measuring peroxiredoxin dimerization and by redox-sensitive fluorescent proteins. Replacing the putative redox-active cysteine residues on AMPK α1 with alanines did not alter the response of AMPK to H2O2. In parallel with measurements of AMPK activity, we measured the cell ATP/ADP ratio. This allowed us to separate the effects on AMPK activity due to ROS production from those caused by changes in this ratio. We conclude that AMPK activity in response to redox changes is not due to direct action on AMPK itself, but is a secondary consequence of redox effects on other processes, such as mitochondrial ATP production.
AU - Hinchy,EC
AU - Gruszczyk,AV
AU - Willows,R
AU - Navaratnam,N
AU - Hall,AR
AU - Bates,G
AU - Bright,TP
AU - Krieg,T
AU - Carling,D
AU - Murphy,MP
DO - 10.1074/jbc.RA118.002579
EP - 17217
PY - 2018///
SN - 0021-9258
SP - 17208
TI - Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly
T2 - JOURNAL OF BIOLOGICAL CHEMISTRY
UR - http://dx.doi.org/10.1074/jbc.RA118.002579
UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000449466500020&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR - http://hdl.handle.net/10044/1/64538
VL - 293
ER -