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

Dan Shao, Shin Ichi Oka, Tong Liu, Peiyong Zhai, Tetsuro Ago, Sebastiano Sciarretta, Hong Li, Junichi Sadoshima

Research output: Contribution to journalArticlepeer-review

111 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)232-245
Number of pages14
JournalCell metabolism
Volume19
Issue number2
DOIs
Publication statusPublished - Feb 4 2014

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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