A Redox-Dependent Mechanism for Regulation of AMPK Activation by Thioredoxin1 during Energy Starvation

Abstract

Summary 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 a 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.

Proteomics Unveils Fibroblast–Cardiomyocyte Lactate Shuttle and Hexokinase Paradox in Mouse Muscles

“…Our studies confirmed the findings of Shao et al 25 that striated muscles, especially the heart muscle, may accelerate glucose uptake under ischemic conditions. Mechanism of this process is based on the thioredoxin1-mediated activation of Prka-dependent translocation of glucose transporters into a cell membrane.…”

“…Such redox-associated mode of glucose uptake stimulation may be critical for cardiac protection against ischemia and is in agreement with the findings of Shao et al 25 showing that heart muscle may accelerate glucose uptake in metabolic stress conditions.…”

PRKAA/AMPK restricts HBV replication through promotion of autophagic degradation

“…36 Recent studies have indicated that the AMPK activity can be regulated by redox modification under oxidative stress. 20 In this study, we found that AMPK was activated by HBVinduced oxidative stress, indicating that virus-induced ROS accumulation could exert a feedback regulation on metabolic stress. TXN, an important reducing enzyme that catalyzes disulfide reduction, serves as a vital cofactor for AMPK activation by preventing the oxidative aggregation of AMPK.…”

“…20 As shown in Figure S5A, H 2 O 2 or diamide (a thiol oxidizing compound) induced a mobility shift of PRKAA in HepG2 cells, which could be reversed by dithiothreitol, a reducing agent that breaks disulfide bonds. However, there was no significant mobility shift of PRKAA in response to HBV-induced oxidative stress (Fig.…”

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…Activation of AMPK in the liver also represses expression of gluconeogenesis enzymes such as Pck1 and G6pc 40 , results opposite from those observed in heme oxygenase-depleted hepatocytes. If the increases in Pck1 and G6pc transcript levels in HO-depleted hepatocytes were due to decreased AMPK activity (perhaps mediated by increased oxidative stress 41 ), transcript levels of genes involved in other anabolic pathways would also be expected to be elevated 42 . However, this was not the case: the expression of key genes involved in lipogenesis, such as sterol regulatory element-binding protein-1, carbohydrate response element-binding protein, acetyl CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase, and glycerol-3-phosphate acyltransferase, was essentially unaltered.…”