scholarly journals Activation of AMPK under Hypoxia: Many Roads Leading to Rome

2020 ◽  
Vol 21 (7) ◽  
pp. 2428 ◽  
Author(s):  
Franziska Dengler
Keyword(s):  
Current Knowledge ◽  
Protective Action ◽  
Energy Levels ◽  
Hypoxia Inducible Factor ◽  
Protective Effects ◽  
Ampk Activation ◽  
Cellular Energy ◽  
Energy Sensor ◽  
Atp Supply ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is known as a pivotal cellular energy sensor, mediating the adaptation to low energy levels by deactivating anabolic processes and activating catabolic processes in order to restore the cellular ATP supply when the cellular AMP/ATP ratio is increased. Besides this well-known role, it has also been shown to exert protective effects under hypoxia. While an insufficient supply with oxygen might easily deplete cellular energy levels, i.e., ATP concentration, manifold other mechanisms have been suggested and are heavily disputed regarding the activation of AMPK under hypoxia independently from cellular AMP concentrations. However, an activation of AMPK preceding energy depletion could induce a timely adaptation reaction preventing more serious damage. A connection between AMPK and the master regulator of hypoxic adaptation via gene transcription, hypoxia-inducible factor (HIF), has also been taken into account, orchestrating their concerted protective action. This review will summarize the current knowledge on mechanisms of AMPK activation under hypoxia and its interrelationship with HIF.

scholarly journals AMPK: a cellular energy sensor primarily regulated by AMP

2014 ◽  
Vol 42 (1) ◽  
pp. 71-75 ◽  
Author(s):  
Graeme J. Gowans ◽  
D. Grahame Hardie
Keyword(s):  
Energy Levels ◽  
Allosteric Activation ◽  
Intact Cells ◽  
Cellular Energy ◽  
Physiological Signal ◽  
The Third ◽  
Energy Sensor ◽  
Primary Signal ◽  
Significant Mechanism ◽  
Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is a cellular energy sensor that monitors the ratio of AMP/ATP, and possibly also ADP/ATP, inside cells. Once activated by falling cellular energy levels, it acts to restore energy homoeostasis by switching on catabolic pathways that generate ATP, while switching off anabolic pathways and other processes consuming ATP. AMPK is switched on by increases in AMP via three mechanisms, all of which are antagonized by ATP: (i) promotion of phosphorylation of Thr172 by upstream activating kinases; (ii) inhibition of dephosphorylation of Thr172 by phosphatases; and (iii) allosteric activation of the phosphorylated kinase. Recently, it has been proposed that the first two mechanisms are also triggered by ADP, which might be the physiological signal rather than AMP, and that the third mechanism may not be physiologically significant. We have re-evaluated these questions, and found that only mechanism (ii) is mimicked by ADP, and that ADP is also less potent than AMP, which we still believe to be the primary signal. We have also provided evidence that mechanism (iii), i.e. allosteric activation by AMP, is a quantitatively significant mechanism in intact cells.

scholarly journals AMPK directly inhibits NDPK through a phosphoserine switch to maintain cellular homeostasis

2012 ◽  
Vol 23 (2) ◽  
pp. 381-389 ◽  
Author(s):  
Rob U. Onyenwoke ◽  
Lawrence J. Forsberg ◽  
Lucy Liu ◽  
Tyisha Williams ◽  
Oscar Alzate ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Phosphorylation Site ◽  
Nucleoside Diphosphate Kinase ◽  
Ampk Activation ◽  
Cellular Energy ◽  
Energy Sensor ◽  
Energy Deprivation ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a key energy sensor that regulates metabolism to maintain cellular energy balance. AMPK activation has also been proposed to mimic benefits of caloric restriction and exercise. Therefore, identifying downstream AMPK targets could elucidate new mechanisms for maintaining cellular energy homeostasis. We identified the phosphotransferase nucleoside diphosphate kinase (NDPK), which maintains pools of nucleotides, as a direct AMPK target through the use of two-dimensional differential in-gel electrophoresis. Furthermore, we mapped the AMPK/NDPK phosphorylation site (serine 120) as a functionally potent enzymatic “off switch” both in vivo and in vitro. Because ATP is usually the most abundant cellular nucleotide, NDPK would normally consume ATP, whereas AMPK would inhibit NDPK to conserve energy. It is intriguing that serine 120 is mutated in advanced neuroblastoma, which suggests a mechanism by which NDPK in neuroblastoma can no longer be inhibited by AMPK-mediated phosphorylation. This novel placement of AMPK upstream and directly regulating NDPK activity has widespread implications for cellular energy/nucleotide balance, and we demonstrate in vivo that increased NDPK activity leads to susceptibility to energy deprivation–induced death.

scholarly journals Adiponectin Facilitates Postconditioning Cardioprotection through Both AMPK-Dependent Nuclear and AMPK-Independent Mitochondrial STAT3 Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-17 ◽  
Author(s):  
Qiqi Zhu ◽  
Haobo Li ◽  
Xiang Xie ◽  
Xiaozhen Chen ◽  
Ramoji Kosuru ◽  
...  
Keyword(s):  
Cell Injury ◽  
Biological Effects ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Ampk Activation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Myocardial Ischemia Reperfusion ◽  
Myocardial Injuries ◽  
Amp Activated Protein Kinase

Myocardial ischemic postconditioning- (IPo-) mediated cardioprotection against myocardial ischemia-reperfusion (IR) injury needs the activation of signal transducer and activator of transcription 3 (STAT3), which involves adiponectin (APN). APN confers its biological effects through AMP-activated protein kinase- (AMPK-) dependent and AMPK-independent pathways. However, the role of AMPK in APN-mediated STAT3 activation in IPo cardioprotection is unknown. We hypothesized that APN-mediated STAT3 activation in IPo is AMPK-independent and that APN through AMPK-dependent STAT3 activation facilitates IPo cardioprotection. Here, Sprague-Dawley rats were subjected to myocardial IR without or with IPo and/or APN. APN or IPo significantly improved postischemic cardiac function and reduced myocardial injury and oxidative stress, and their combination further attenuated postischemic myocardial injuries. APN or its combination with IPo but not IPo alone significantly increased AMPK activation and both nuclear and mitochondrial STAT3 activation, while IPo significantly enhanced mitochondrial but not nuclear STAT3 activation. In primarily isolated cardiomyocytes, recombined globular APN (gAd), hypoxic postconditioning (HPo), or their combination significantly attenuated hypoxia/reoxygenation-induced cell injury and increased nuclear and/or mitochondrial STAT3 activation. STAT3 inhibition had no impact on gAd or gAd in combination with HPo-induced AMPK activation but abolished their cellular protective effects. AMPK inhibition did not affect HPo cardioprotection but abolished gAd cardioprotection and disabled gAd to facilitate/enhance HPo cardioprotection and STAT3 activation. These results suggest that APN confers cardioprotection through AMPK-dependent and AMPK-independent STAT3 activation, while IPo confers cardioprotection through AMPK-independent mitochondrial STAT3 activation. Joint use of APN and IPo synergistically attenuated myocardial IR injury by activating STAT3 via distinct signaling pathways.

Fish oil supplementation inhibits endoplasmic reticulum stress and improves insulin resistance: involvement of AMP-activated protein kinase

2017 ◽  
Vol 8 (4) ◽  
pp. 1481-1493 ◽  
Author(s):  
Wenqi Yang ◽  
Xu Chen ◽  
Ming Chen ◽  
Yanping Li ◽  
Qing Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Endoplasmic Reticulum Stress ◽  
Fish Oil ◽  
Er Stress ◽  
Protective Effects ◽  
Ampk Activation ◽  
Amp Activated Protein Kinase ◽  
Fish Oil Supplementation

ER stress inhibition through AMPK activation may explain the protective effects of fish oil against HFD-induced insulin resistance.

scholarly journals Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes

2006 ◽  
Vol 203 (7) ◽  
pp. 1665-1670 ◽  
Author(s):  
Peter Tamás ◽  
Simon A. Hawley ◽  
Rosemary G. Clarke ◽  
Kirsty J. Mustard ◽  
Kevin Green ◽  
...  
Keyword(s):  
Protein Kinase ◽  
T Lymphocytes ◽  
Energy Homeostasis ◽  
Antigen Receptor ◽  
Adenosine Monophosphate ◽  
Ampk Activation ◽  
Serine Kinase ◽  
Cellular Energy ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of

The adenosine monophosphate (AMP)–activated protein kinase (AMPK) has a crucial role in maintaining cellular energy homeostasis. This study shows that human and mouse T lymphocytes express AMPKα1 and that this is rapidly activated in response to triggering of the T cell antigen receptor (TCR). TCR stimulation of AMPK was dependent on the adaptors LAT and SLP76 and could be mimicked by the elevation of intracellular Ca2+ with Ca2+ ionophores or thapsigargin. AMPK activation was also induced by energy stress and depletion of cellular adenosine triphosphate (ATP). However, TCR and Ca2+ stimulation of AMPK required the activity of Ca2+–calmodulin-dependent protein kinase kinases (CaMKKs), whereas AMPK activation induced by increased AMP/ATP ratios did not. These experiments reveal two distinct pathways for the regulation of AMPK in T lymphocytes. The role of AMPK is to promote ATP conservation and production. The rapid activation of AMPK in response to Ca2+ signaling in T lymphocytes thus reveals that TCR triggering is linked to an evolutionally conserved serine kinase that regulates energy metabolism. Moreover, AMPK does not just react to cellular energy depletion but also anticipates it.

scholarly journals AMPK: a balancer of the renin–angiotensin system

2019 ◽  
Vol 39 (9) ◽  
Author(s):  
Jia Liu ◽  
Xuan Li ◽  
Qingguo Lu ◽  
Di Ren ◽  
Xiaodong Sun ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Recent Literature ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Cellular Energy ◽  
Arterial Blood ◽  
Energy Sensor ◽  
Cellular Pathways ◽  
Amp Activated Protein Kinase

Abstract The renin–angiotensin system (RAS) is undisputedly well-studied as one of the oldest and most critical regulators for arterial blood pressure, fluid volume, as well as renal function. In recent studies, RAS has also been implicated in the development of obesity, diabetes, hyperlipidemia, and other diseases, and also involved in the regulation of several signaling pathways such as proliferation, apoptosis and autophagy, and insulin resistance. AMP-activated protein kinase (AMPK), an essential cellular energy sensor, has also been discovered to be involved in these diseases and cellular pathways. This would imply a connection between the RAS and AMPK. Therefore, this review serves to draw attention to the cross-talk between RAS and AMPK, then summering the most recent literature which highlights AMPK as a point of balance between physiological and pathological functions of the RAS.

AMP kinase (PRKAA1)

2014 ◽  
Vol 67 (9) ◽  
pp. 758-763 ◽  
Author(s):  
Sukriti Krishan ◽  
Des R Richardson ◽  
Sumit Sahni
Keyword(s):  
Energy Homeostasis ◽  
Atp Synthesis ◽  
Cellular Growth ◽  
Α Subunit ◽  
Cellular Energy ◽  
Therapeutic Drugs ◽  
Energy Sensor ◽  
Energy Consuming ◽  
Cardiac Disorders ◽  
Amp Activated Protein Kinase

The PRKAA1 gene encodes the catalytic α-subunit of 5′ AMP-activated protein kinase (AMPK). AMPK is a cellular energy sensor that maintains energy homeostasis within the cell and is activated when the AMP/ATP ratio increases. When activated, AMPK increases catabolic processes that increase ATP synthesis and inhibit anabolic processes that require ATP. Additionally, AMPK also plays a role in activating autophagy and inhibiting energy consuming processes, such as cellular growth and proliferation. Due to its role in energy metabolism, it could act as a potential target of many therapeutic drugs that could be useful in the treatment of several diseases, for example, diabetes. Moreover, AMPK has been shown to be involved in inhibiting tumour growth and metastasis, and has also been implicated in the pathology of neurodegenerative and cardiac disorders. Hence, a better understanding of AMPK and its role in various pathological conditions could enable the development of strategies to use it as a therapeutic target.

Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration

2007 ◽  
Vol 293 (1) ◽  
pp. H457-H466 ◽  
Author(s):  
Li Zhang ◽  
Huamei He ◽  
James A. Balschi
Keyword(s):  
Protein Kinase ◽  
Isolated Heart ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Cellular Energy ◽  
Rat Hearts ◽  
Energy Sensor ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase ◽  
Krebs Henseleit Buffer

AMP-activated protein kinase (AMPK) acts as a cellular energy sensor: it responds to an increase in AMP concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP). Metformin and phenformin, which are biguanides, have been reported to increase AMPK activity without increasing AMP/ATP. This study tests the hypothesis that these biguanides increase AMPK activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts ( n = 5–7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM phenformin or 10 mM metformin, and 31P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times, hearts were freeze-clamped and assayed for AMPK activity, phosphorylation of Thr172 on AMPK-α, and phosphorylation of Ser79 on acetyl-CoA carboxylase, an AMPK target. In hearts treated with phenformin for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and AMPK activity was elevated at 36 min. In hearts treated with metformin, [AMP] was increased at 50 min and AMPK activity, phosphorylated AMPK, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min. In metformin-treated hearts, HPLC-measured total AMP content and total AMP/ATP did not increase. In summary, phenformin and metformin increase AMPK activity and phosphorylation in the isolated heart. The increase in AMPK activity was always preceded by and correlated with increased cytosolic [AMP]. Total AMP content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active AMP, which triggered increased AMPK activity, but measures of total AMP did not.

scholarly journals Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKα2 but not AMPKα1

2006 ◽  
Vol 290 (5) ◽  
pp. E780-E788 ◽  
Author(s):  
Kei Sakamoto ◽  
Elham Zarrinpashneh ◽  
Grant R. Budas ◽  
Anne-Catherine Pouleur ◽  
Anindya Dutta ◽  
...  
Keyword(s):  
Cardiac Muscle ◽  
Crucial Role ◽  
Morphological Analysis ◽  
Energy Levels ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Cellular Energy ◽  
Basal Activity ◽  
Upstream Kinase ◽  
Amp Activated Protein Kinase

Recent studies indicate that the LKB1 is a key regulator of the AMP-activated protein kinase (AMPK), which plays a crucial role in protecting cardiac muscle from damage during ischemia. We have employed mice that lack LKB1 in cardiac and skeletal muscle and studied how this affected the activity of cardiac AMPKα1/α2 under normoxic, ischemic, and anoxic conditions. In the heart lacking cardiac muscle LKB1, the basal activity of AMPKα2 was vastly reduced and not increased by ischemia or anoxia. Phosphorylation of AMPKα2 at the site of LKB1 phosphorylation (Thr172) or phosphorylation of acetyl-CoA carboxylase-2, a downstream substrate of AMPK, was ablated in ischemic heart lacking cardiac LKB1. Ischemia was found to increase the ADP-to-ATP (ADP/ATP) and AMP-to-ATP ratios (AMP/ATP) to a greater extent in LKB1-deficient cardiac muscle than in LKB1-expressing muscle. In contrast to AMPKα2, significant basal activity of AMPKα1 was observed in the lysates from the hearts lacking cardiac muscle LKB1, as well as in cardiomyocytes that had been isolated from these hearts. In the heart lacking cardiac LKB1, ischemia or anoxia induced a marked activation and phosphorylation of AMPKα1, to a level that was only moderately lower than observed in LKB1-expressing heart. Echocardiographic and morphological analysis of the cardiac LKB1-deficient hearts indicated that these hearts were not overtly dysfunctional, despite possessing a reduced weight and enlarged atria. These findings indicate that LKB1 plays a crucial role in regulating AMPKα2 activation and acetyl-CoA carboxylase-2 phosphorylation and also regulating cellular energy levels in response to ischemia. They also provide genetic evidence that an alternative upstream kinase can activate AMPKα1 in cardiac muscle.

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