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.

A redox-dependent mechanism for regulation of AMPK activation by thioredoxin1 during energy starvation / Shao, Dan; Oka, Shin Ichi; Liu, Tong; Zhai, Peiyong; Ago, Tetsuro; Sciarretta, Sebastiano; Li, Hong; Sadoshima, Junichi. - In: CELL METABOLISM. - ISSN 1550-4131. - STAMPA. - 19:2(2014), pp. 232-245. [10.1016/j.cmet.2013.12.013]

A redox-dependent mechanism for regulation of AMPK activation by thioredoxin1 during energy starvation

SCIARRETTA, SEBASTIANO;
2014

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.
2014
AMP-Activated Protein Kinases; Animals; Immunoblotting; Immunoprecipitation; Mass Spectrometry; Mice; Mice, Transgenic; Models, Biological; Oxidation-Reduction; Phosphorylation; Thioredoxins; Cell Biology; Molecular Biology; Physiology
01 Pubblicazione su rivista::01a Articolo in rivista
A redox-dependent mechanism for regulation of AMPK activation by thioredoxin1 during energy starvation / Shao, Dan; Oka, Shin Ichi; Liu, Tong; Zhai, Peiyong; Ago, Tetsuro; Sciarretta, Sebastiano; Li, Hong; Sadoshima, Junichi. - In: CELL METABOLISM. - ISSN 1550-4131. - STAMPA. - 19:2(2014), pp. 232-245. [10.1016/j.cmet.2013.12.013]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/809323
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