The Regulation of AMP-Activated Protein Kinase by H2O2
Abstract
AMP-activated protein kinase (AMPK), a heterotrimeric serine/threonine kinase, is activated by conditions leading to an increase of the intracellular AMP:ATP ratio. However, how AMPK is regulated under the oxidative stress is completely unknown. In the present study, we examined effects of the oxidative agent H(2)O(2) on AMPK. AMPK was transiently and concentration-dependently activated by H(2)O(2) in NIH-3T3 cells. This activation was tightly associated with an increased AMP:ATP ratio, an electrophoretic mobility shift of AMPK alpha1 catalytic subunit, and an increased phosphorylation level of AMPK alpha1 threonine 172, which is a major in vitro phosphorylation site by the upstream AMPK kinase. All of these events were significantly blocked by the pretreatment of 0.5% dimethyl sulfoxide, a potent hydroxyl radical scavenger, indicating that AMPK cascades are highly sensitive to the oxidative stress. Interestingly, a specific tyrosine kinase inhibitor, genistein, further stimulated the H(2)O(2)-induced AMPK activity by 70% without altering the AMP:ATP. Taken together, our results suggest that AMP:ATP ratio is the major parameter to which AMPK responds under the oxidative stress, but AMPK may be regulated in part by a tyrosine kinase-dependent pathway, which is independent of the cellular adenosine nucleotides level.
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AMPK is responsive to imbalanced redox status.
“Recent lines of evidence have demonstrated AMPK responsiveness to imbalanced redox status, thus bringing new insights into the networks of redox-stimulated signals upstream of AMPK (Table 1) [42,43,44,45,46,47,48,49,50,51].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [45]
In NIH-3T3 cells, exogenous hydrogen peroxide transiently activated AMPK in a dose-dependent manner, associated with an increased AMP-to-ATP ratio.
“Similarly, in NIH-3T3 cells, exogenous hydrogen peroxide transiently activated AMPK in a dose-dependent manner, which was associated with an increased AMP-to-ATP ratio [45].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [45]
H2O2 appears to activate AMPK through an increase in the AMP/ATP ratio and by threonine phosphorylation.
“H2O2 appears to activate AMPK through an increase in the AMP/ATP ratio and by threonine phosphorylation (60).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [60]
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“ROS are recognized to function as signaling molecules in many systems (5, 18, 40) and might also plausibly regulate the balance between myocardial oxygen demand and delivery.”
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Guo, Q., Wang, S., Zhang, S., Xu, H., Li, X., Guan, Y., Yi, F., Zhou, T., Jiang, B., Bai, N., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2019103111 · Cited by 149 · see citing works
“Previous studies have shown that AMPK is not only an energy sensor, but also subject to regulation by ROS (Choi et al , 2001).”
Kala, M., Shaikh, M. V., & Nivsarkar, M. (2016) · Reproductive Medicine and Biology · doi:10.1002/rmb2.12013 · Cited by 146 · see citing works
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RetractedAβ-induced formation of autophagosomes is mediated by RAGE-CaMKKβ-AMPK signaling
Son, S. M., Jung, E. S., Shin, H. J., Byun, J., & Mook‐Jung, I. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.09.039 · Cited by 140 · see citing works
Tzatsos, A., & Tsichlis, P. N. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610101200 · Cited by 139 · see citing works
Activation of AMPK under Hypoxia: Many Roads Leading to Rome
Dengler, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072428 · Cited by 133 · see citing works
“Due to the harmful accumulation of ROS, the AMP/ATP ratio could be increased, thus leading to an activation of AMPK [73,74], whereas others report the AMP concentration to be unchanged after hypoxia-induced ROS formation and AMPK activation [41,55,60,71].”
BackgroundHigaki, Y., Mikami, T., Fujii, N., Hirshman, M. F., Koyama, K., Seino, T., Tanaka, K., & Goodyear, L. J. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00150.2007 · Cited by 138 · see citing works
Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease
Sid, B., Verrax, J., & Calderón, P. B. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.05.007 · Cited by 137 · see citing works
Toyoda, T., Hayashi, T., Miyamoto, L., Yonemitsu, S., Nakano, M. H., Tanaka, S., Ebihara, K., Masuzaki, H., Hosoda, K., Inoue, G., et al. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00487.2003 · Cited by 137 · see citing works
“In support of our observations, previous studies have shown that H2O2 induces a large increase in AMPK activity in NIH-3T3 cells (9), and peroxynitrite increases the phosphorylation of ACC and AMPK in bovine aortic endothelial cells (BAEC) (58, 59).”
The Relationship of Redox With Hallmarks of Cancer: The Importance of Homeostasis and Context
Xing, F., Hu, Q., Qin, Y., Xu, J., Zhang, B., Yu, X., & Wang, W. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.862743 · Cited by 136 · see citing works
“AMPK is sensitive to ROS and can be phosphorylated by the upstream kinase AMPK kinase (AMPKK) following H2O2 accumulation (106).”
BackgroundOxidative stress activates AMPK in cultured cells primarily by increasing cellular AMP and/or ADP
Auciello, F. R., Ross, F. A., Ikematsu, N., & Hardie, D. G. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.07.025 · Cited by 136 · see citing works
“The effects of increased AMP were partly due to inhibition of Thr172 dephosphorylation.”
BackgroundMarino, A., Hausenloy, D. J., Andreadou, I., Horman, S., Bertrand, L., & Beauloye, C. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.02.047 · Cited by 134 · see citing works
“depending on AMP, ADP, and Ca2+, AMPK can be activated by unconventional pathways, including ischemia [19,23], hypoxia [24], oxidant signaling [25,26], hormones [27,28], DNA damage [29], and cytokines [30,31].”
BackgroundExercise and mitochondrial dynamics: keeping in shape with ROS and AMPK
Trewin, A., Berry, B., & Wojtovich, A. (2018) · Antioxidants · doi:10.3390/antiox7010007 · Cited by 129 · see citing works
“that the exposure of 100–600 μM exogenous H2O2 increased AMPK activity due to an H2O2 induced increase in the AMP:ATP ratio [82].”
BackgroundPirinen, E., Kuulasmaa, T., Pietilä, M., Heikkinen, S., Tusa, M., Itkonen, P., Boman, S., Skommer, J., Virkamäki, A., Hohtola, E., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.02034-06 · Cited by 135 · see citing works
“In addition, hydrogen peroxide can activate AMPK by reducing the ATP/AMP ratio in NIH 3T3-L1 fibroblasts ( 9 ).”
BackgroundChambers, M. A., Moylan, J. S., Smith, J. D., Goodyear, L. J., & Reid, M. B. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2008.165639 · Cited by 132 · see citing works
“AMPK is thought to be regulated by factors that change the ratio of AMP : ATP such as hypoxia, heat shock, metabolic toxicity, exogenous ROS (Choi et al. 2001; Musi et al. 2001a; Fryer et al. 2002) and exercise (Musi et al.”
BackgroundMolecular Interactions Between Reactive Oxygen Species and Autophagy in Kidney Disease
Kaushal, G. P., Chandrashekar, K., & Juncos, L. A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20153791 · Cited by 129 · see citing works
Redox basis of exercise physiology
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“Regarding AMPK, Choi and colleagues [238] demonstrated that AMPK becomes activated under oxidative stress conditions induced by H2O2 and this is mediated by energy disturbance (AMP:ATP ratio) [238].”
BackgroundChiang, M., Cheng, Y., Chen, S., Yen, C., & Huang, R. (2016) · Experimental Cell Research · doi:10.1016/j.yexcr.2016.08.013 · Cited by 124 · see citing works
The role of oxidative stress in the development of alcoholic liver disease
Galicia‐Moreno, M., & Gutiérrez‐Reyes, G. (2014) · Revista de Gastroenterología de México (English Edition) · doi:10.1016/j.rgmxen.2014.06.007 · Cited by 118 · see citing works
“Moreover, the first studies demonstrating the effects of oxidative stress on AMPK activation were carried out more than 10 years ago, when Choi et al.(77) showed that the AMPK cascade was highly sensitive to ROS.”
BackgroundRegulation of NAD(P)H oxidases by AMPK in cardiovascular systems
Song, P., & Zou, M. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.01.025 · Cited by 119 · see citing works
Sanchez, A. M. J., Candau, R. B., Csibi, A., Pagano, A. F., Raibon, A., & Bernardi, H. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00125.2012 · Cited by 116 · see citing works
The Beneficial Effects of Principal Polyphenols from Green Tea, Coffee, Wine, and Curry on Obesity
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“EGCG significantly decreased blood circulating interleukin (IL)-6, tumor necrosis factor-α (TNF)-α, ROS, and superoxide dismutase (SOD) levels.”
BackgroundInfluentialAMP‐ACTIVATED PROTEIN KINASE ACTIVATION AS A STRATEGY FOR PROTECTING VASCULAR ENDOTHELIAL FUNCTION
Zou, M., & Wu, Y. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04851.x · Cited by 115 · see citing works
Iron Regulation of Pancreatic Beta-Cell Functions and Oxidative Stress
Backe, M. B., Moen, I. W., Ellervik, C., Hansen, J. B., & Mandrup-Poulsen, T. R. (2016) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071715-050939 · Cited by 116 · see citing works
“However, at least two possible pathways of iron-mediated regulation of AMPK activity exist: Either (a) AMPK acts as a redox sensor and is therefore regulated by ROS formed by the LIP, or (b) AMPK is regulated directly by the activity of the ETC that is in turn dependent on cellular iron content (34, 185).”
BackgroundThe double-edged sword of AMPK signaling in cancer and its therapeutic implications
Jeon, S., & Hay, N. (2015) · Archives of Pharmacal Research · doi:10.1007/s12272-015-0549-z · Cited by 115 · see citing works
“The first report demonstrating that exogenous H2O2 can activate AMPK in cultured cells was published more than 10 years ago (Choi et al. 2001).”
BackgroundCompound C inhibits hypoxic activation of HIF‐1 independent of AMPK
Emerling, B. M., Viollet, B., Tormos, K. V., & Chandel, N. S. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.11.038 · Cited by 112 · see citing works
The Octamer Binding Transcription Factor Oct-1 Is a Stress Sensor
Tantin, D. R., Schild‐Poulter, C., Wang, V. E. H., Haché, R. J. G., & Sharp, P. A. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2399 · Cited by 112 · see citing works
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Nutrient-sensing mTORC1: Integration of metabolic and autophagic signals
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Park, C.-E., Yun, H., Lee, E.-B., Min, B.-I., Bae, H., Choe, W., Kang, I., Kim, S. S., & Ha, J. (2010) · Journal of Medicinal Food · doi:10.1089/jmf.2009.1359 · Cited by 109 · see citing works
“15,16 We have demonstrated that genistein activates AMPK in adipocytes and HT29 colon cancer cells.”
Telomere attrition: metabolic regulation and signalling function?
Casagrande, S., & Hau, M. (2019) · Biology Letters · doi:10.1098/rsbl.2018.0885 · Cited by 109 · see citing works
Pandey, A. N., Tripathi, A., Premkumar, K. V., Shrivastav, T. G., & Chaube, S. K. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22736 · Cited by 105 · see citing works
“However, few studies indicate that H2O2 and other oxidative stress inducers stimulate AMPactivated protein kinase (AMPK) [Choi et al., 2001; Chen et al., 2006; Chen and Downs, 2008].”
BackgroundRegulation of Glycogen Synthase by Glucose and Glycogen
Halse, R., Fryer, L. G. D., McCormack, J. G., Carling, D., & Yeaman, S. J. (2003) · Diabetes · doi:10.2337/diabetes.52.1.9 · Cited by 103 · see citing works
“Cells in normal glucose conditions were also treated with hydrogen peroxide, another known activator of AMPK (32), to further examine the role of this enzyme in modulating GS activity (Fig.”
MethodBułdak, Ł., Łabuzek, K., Bułdak, R. J., Kozłowski, M., Machnik, G., Liber, S., Suchy, D., Duława, A., & Okopień, B. (2014) · Pharmacological Reports · doi:10.1016/j.pharep.2013.11.008 · Cited by 104 · see citing works
Noise-induced loss of sensory hair cells is mediated by ROS/AMPKα pathway
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“A contributory role of ROS species on the long-term activation of AMPK in beta cells can, however, not be excluded [66].”
An, Z., Wang, H., Song, P., Zhang, M., Geng, X., & Zou, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703701200 · Cited by 97 · see citing works
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Glucose Autoregulates Its Uptake in Skeletal Muscle
Itani, S. I., Saha, A. K., Kurowski, T. G., Coffin, H. R., Tornheim, K., & Ruderman, N. B. (2003) · Diabetes · doi:10.2337/diabetes.52.7.1635 · Cited by 96 · see citing works
“AMPK is a ubiquitously expressed enzyme whose activity is increased when cells are exposed to such stresses as hypoxia, hyperosmolarity (4), fuel deprivation (5,6), reactive O2 species (7), and, in muscle, contraction (exercise) (8–10).”
BackgroundThe mitochondrial permeability transition: Nexus of aging, disease and longevity
Rottenberg, H., & Hoek, J. B. (2021) · Cells · doi:10.3390/cells10010079 · Cited by 94 · see citing works
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Reactive Oxygen Species Regulation of Autophagy in Skeletal Muscles
Rahman, M., Mofarrahi, M., Kristof, A. S., Nkengfac, B., Harel, S., & Hussain, S. N. A. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5410 · Cited by 91 · see citing works
“Both AMPK and mTORC1 are well known to be under the influence of ROS (7, 41, 46).”
Jiang, H., Meng, X., Zhang, N., Ge, H., Wei, J., Qian, K., Yang, Z., Park, Y., Palli, S. R., & Wang, J. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2214038120 · Cited by 89 · see citing works
“Because oxidative stress-induced ATP depletion can activate AMPK (41, 49), we next detected the malondialdehyde (MDA) and ATP levels after exposure to deltamethrin.”
BackgroundEvidence of cancer‐promoting roles for AMPK and related kinases
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“Treatment of cells with exogenous H2O2 likewise activates AMPK [21].”
BackgroundSanati, M., Afshari, A. R., Kesharwani, P., Sukhorukov, V. N., & Sahebkar, A. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.05.035 · Cited by 93 · see citing works
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Torres, F., González‐Candia, A., Montt, C., Ebensperger, G., Chubretovic, M., Serón‐Ferré, M., Reyes, R. V., Llanos, A. J., & Herrera, E. A. (2015) · Journal of Pineal Research · doi:10.1111/jpi.12222 · Cited by 85 · see citing works
“diphosphoribose (cADPR) [22], activate AMP kinase [23], and increase phosphodiesterase-5 (PDE5) activity [24] in pulmonary vascular smooth muscle cells.”
BackgroundZhang, M., Dong, Y., Xu, J., Xie, Z., Wu, Y., Song, P., Guzman, M., Wu, J., & Zou, M.-H. (2008) · Circulation Research · doi:10.1161/circresaha.107.163253 · Cited by 82 · see citing works
“In addition, AMPK is activated by exogenous hydrogen peroxide (H2O2).(6,28) Thromboxane (Tx)A2 is a product of arachidonic acid through the cyclooxygenase pathway and is synthesized after activation of a variety of cells, including platelets, vascular smooth muscle cells (VSMCs), endothelial cells, and macrophages.”
BackgroundLiu, C., Liang, B., Wang, Q., Wu, J., & Zou, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.102491 · Cited by 82 · see citing works
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“Although AMPK has also been shown to be sensitive to oxidative stress [34], its involvement in cancer metastasis is somewhat dependent on the type of stimulus and oxidative conditions.”
Sundararaman, A., Amirtham, U., & Rangarajan, A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.731257 · Cited by 80 · see citing works
“Activation of AMPK can also occur in response to oxidative stress (13).”
Background5??? Adenosine Monophosphate-Activated Protein Kinase, Metabolism and Exercise
Aschenbach, W. G., Sakamoto, K., & Goodyear, L. J. (2004) · Sports Medicine · doi:10.2165/00007256-200434020-00003 · Cited by 80 · see citing works
- Authors
- Choi, S.-L., Kim, S.-J., Lee, K.-T., Kim, J., Mu, J., Birnbaum, M. J., Soo Kim, S., & Ha, J.
- Affiliations
- Kyung Hee University (KR)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Ha, Joohun
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2001-09
- Volume
- 287
- Issue
- 1
- Pages
- 92-97
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2090321764
- Cited by
- 294
- References
- 44
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 10 · 2023: 9 · 2022: 14 · 2021: 11 · 2020: 19 · 2019: 13 · 2018: 6 · 2017: 6 · 2016: 16 · 2015: 15 · 2014: 15 · 2013: 20 · 2012: 20
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- AMPK, hydrogen peroxide, oxidative stress, AMP/ATP ratio, hydroxyl radical scavenging, dimethyl sulfoxide, genistein, tyrosine kinase, kinase activation
- MeSH terms
- Adenosine Monophosphate, Adenosine Triphosphate, Animals, Catalysis, Enzyme Activation, Hydrogen Peroxide, Multienzyme Complexes, Phosphorylation, Protein-Tyrosine Kinases, Threonine, 3T3 Cells, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Oxidative Stress, Mice, AMP-Activated Protein Kinases
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