title: A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation.
abstract: 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.
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA.
authors: Dan
authors: D
authors: Shao
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA.
authors: Shin-Ichi
authors: S
authors: Oka
authors: Center for Advanced Proteomics Research and Department of Biochemistry and Molecular Biology, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA.
authors: Tong
authors: T
authors: Liu
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA.
authors: Peiyong
authors: P
authors: Zhai
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA.
authors: Tetsuro
authors: T
authors: Ago
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA.
authors: Sebastiano
authors: S
authors: Sciarretta
authors: Center for Advanced Proteomics Research and Department of Biochemistry and Molecular Biology, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA.
authors: Hong
authors: H
authors: Li
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA. Electronic address: sadoshju@njms.rutgers.edu.
authors: Junichi
authors: J
authors: Sadoshima
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010084:Oxidation-Reduction; D010766:Phosphorylation; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D013879:Thioredoxins; D055372:AMP-Activated Protein Kinases