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A Redox-Dependent Mechanism for Regulation of AMPK Activation by Thioredoxin1 during Energy Starvation
Open accessAbstract
5'-AMP-activated protein kinase (AMPK) is a key regulator of metabolism and survival during energy stress. Dysregulation of AMPK is strongly associated with oxidative-stress-related disease. However, whether and how AMPK is regulated by intracellular redox status remains unknown. Here we show that the activity of AMPK is negatively regulated by oxidation of Cys130 and Cys174 in its α subunit, which interferes with the interaction between AMPK and AMPK kinases (AMPKK). Reduction of Cys130/Cys174 is essential for activation of AMPK during energy starvation. Thioredoxin1 (Trx1), an important reducing enzyme that cleaves disulfides in proteins, prevents AMPK oxidation, serving as an essential cofactor for AMPK activation. High-fat diet consumption downregulates Trx1 and induces AMPK oxidation, which enhances cardiomyocyte death during myocardial ischemia. Thus, Trx1 modulates activation of the cardioprotective AMPK pathway during ischemia, functionally linking oxidative stress and metabolism in the heart.
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“HFD-induced AMPK deficiency contributed to the enhanced cardiomyocyte death in myocardial ischemia [267].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [267]
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Metadata
- Authors
- Shao, D., Oka, S.-I., Liu, T., Zhai, P., Ago, T., Sciarretta, S., Li, H., & Sadoshima, J.
- Affiliations
- Rutgers Health (US)
- Corresponding author
- Sadoshima, Junichi
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 19
- Issue
- 2
- Pages
- 232-245
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3937768
- OpenAlex
- W1980239332
- Cited by
- 252
- References
- 32
- Citations by year
- 2026: 21 · 2025: 18 · 2024: 17 · 2023: 14 · 2022: 19 · 2021: 39 · 2020: 22 · 2019: 24 · 2018: 20 · 2017: 18 · 2016: 18 · 2015: 12 · 2014: 10
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service
- National Institute on Aging (AG23039, R01AG023039)
- National Heart, Lung, and Blood Institute (HL91469, R01HL067724, HL102738, R01HL102738, R01HL112330, HL-67724, R01HL091469, HL112330)
- National Institute of Neurological Disorders and Stroke (NS 046593, P30NS046593)
- 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
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- AMPK activation, redox regulation, cysteine oxidation, energy starvation, oxidative stress, high-fat diet, cardiomyocyte death, myocardial ischemia, myocardial metabolism, disulfide bond reduction
- MeSH terms
- Animals, Mice, Transgenic, Models, Biological, Oxidation-Reduction, Phosphorylation, Mass Spectrometry, Thioredoxins, Immunoblotting, Immunoprecipitation, Mice, AMP-Activated Protein Kinases
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