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Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly

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Title: Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly
Authors: Hinchy, EC
Gruszczyk, AV
Willows, R
Navaratnam, N
Hall, AR
Bates, G
Bright, TP
Krieg, T
Carling, D
Murphy, MP
Item Type: Journal Article
Abstract: 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.
Issue Date: 2-Nov-2018
Date of Acceptance: 10-Sep-2018
URI: http://hdl.handle.net/10044/1/64538
DOI: https://dx.doi.org/10.1074/jbc.RA118.002579
ISSN: 0021-9258
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Start Page: 17208
End Page: 17217
Journal / Book Title: JOURNAL OF BIOLOGICAL CHEMISTRY
Volume: 293
Issue: 44
Copyright Statement: © 2018 Hinchy et al. Final version open access under the terms of the Creative Commons CC-BY license (https://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
AMP-activated kinase (AMPK)
reactive oxygen species (ROS)
mitochondria
hydrogen peroxide
redox signaling
HYDROGEN-PEROXIDE
ENERGY SENSOR
REPERFUSION INJURY
MECHANISMS
PEROXIREDOXIN
CELLS
HOMEOSTASIS
STRESS
MUSCLE
ADP
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Publication Status: Published
Open Access location: http://www.jbc.org/content/293/44/17208.long
Online Publication Date: 2018-09-19
Appears in Collections:Clinical Sciences
Molecular Sciences



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