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  1. Article ; Online: Staving off cell death.

    Hardie, D Grahame

    Science (New York, N.Y.)

    2023  Volume 380, Issue 6652, Page(s) 1322–1323

    Abstract: A signaling pathway that senses energy stress opposes necroptotic cell death. ...

    Abstract A signaling pathway that senses energy stress opposes necroptotic cell death.
    MeSH term(s) Signal Transduction ; Necroptosis ; Energy Metabolism ; Humans
    Language English
    Publishing date 2023-06-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.adi6827
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  2. Article ; Online: 100 years of the Warburg effect: a historical perspective.

    Hardie, D Grahame

    Endocrine-related cancer

    2022  Volume 29, Issue 12, Page(s) T1–T13

    Abstract: Otto Warburg published the first paper describing what became known as the Warburg effect in 1923. All that was known about glucose metabolism at that time was that it occurred in two stages: (i) fermentation (glycolysis) in which glucose was converted ... ...

    Abstract Otto Warburg published the first paper describing what became known as the Warburg effect in 1923. All that was known about glucose metabolism at that time was that it occurred in two stages: (i) fermentation (glycolysis) in which glucose was converted to lactate, which did not require oxygen, and (ii) oxidative metabolism, in which the carbon atoms derived from glycolysis were fully oxidized to carbon dioxide, which did require oxygen. Warburg discovered that most tumour tissues produced a large amount of lactate that was reduced but not eliminated in the presence of oxygen, while most normal tissues produced a much smaller amount of lactate that was eliminated by the provision of oxygen. These findings were clearly well ahead of their time because it was another 80 years before they were to have any major impact, and even today the mechanisms underlying the Warburg effect are not completely understood.
    MeSH term(s) Carbon Dioxide ; Glucose/metabolism ; Glycolysis ; Humans ; Lactic Acid/metabolism ; Neoplasms/metabolism ; Oxygen
    Chemical Substances Carbon Dioxide (142M471B3J) ; Lactic Acid (33X04XA5AT) ; Glucose (IY9XDZ35W2) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2022-10-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1218450-0
    ISSN 1479-6821 ; 1351-0088
    ISSN (online) 1479-6821
    ISSN 1351-0088
    DOI 10.1530/ERC-22-0173
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: AMP-activated protein kinase - a journey from 1 to 100 downstream targets.

    Hardie, D Grahame

    The Biochemical journal

    2022  Volume 479, Issue 22, Page(s) 2327–2343

    Abstract: A casual decision made one evening in 1976, in a bar near the Biochemistry Department at the University of Dundee, led me to start my personal research journey by following up a paper that suggested that acetyl-CoA carboxylase (ACC) (believed to be a key ...

    Abstract A casual decision made one evening in 1976, in a bar near the Biochemistry Department at the University of Dundee, led me to start my personal research journey by following up a paper that suggested that acetyl-CoA carboxylase (ACC) (believed to be a key regulatory enzyme of fatty acid synthesis) was inactivated by phosphorylation by what appeared to be a novel, cyclic AMP-independent protein kinase. This led me to define and name the AMP-activated protein kinase (AMPK) signalling pathway, on which I am still working 46 years later. ACC was the first known downstream target for AMPK, but at least 100 others have now been identified. This article contains some personal reminiscences of that research journey, focussing on: (i) the early days when we were defining the kinase and developing the key tools required to study it; (ii) the late 1990s and early 2000s, an exciting time when we and others were identifying the upstream kinases; (iii) recent times when we have been studying the complex role of AMPK in cancer. The article is published in conjunction with the Sir Philip Randle Lecture of the Biochemical Society, which I gave in September 2022 at the European Workshop on AMPK and AMPK-related kinases in Clydebank, Scotland. During the early years of my research career, Sir Philip acted as a role model, due to his pioneering work on insulin signalling and the regulation of pyruvate dehydrogenase.
    MeSH term(s) AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Protein Serine-Threonine Kinases ; Multienzyme Complexes/metabolism ; Acetyl-CoA Carboxylase/metabolism ; Phosphorylation
    Chemical Substances AMP-Activated Protein Kinases (EC 2.7.11.31) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Multienzyme Complexes ; Acetyl-CoA Carboxylase (EC 6.4.1.2)
    Language English
    Publishing date 2022-11-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20220255
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  4. Article ; Online: AMPK promotes lysosomal and mitochondrial biogenesis via folliculin:FNIP1.

    Freemantle, Jordana B / Hardie, D Grahame

    Life metabolism

    2023  Volume 2, Issue 5, Page(s) load027

    Abstract: The AMP-activated protein kinase (AMPK) is known to maintain the integrity of cellular mitochondrial networks by (i) promoting fission, (ii) inhibiting fusion, (iii) promoting recycling of damaged components via mitophagy, (iv) enhancing lysosomal ... ...

    Abstract The AMP-activated protein kinase (AMPK) is known to maintain the integrity of cellular mitochondrial networks by (i) promoting fission, (ii) inhibiting fusion, (iii) promoting recycling of damaged components via mitophagy, (iv) enhancing lysosomal biogenesis to support mitophagy, and (v) promoting biogenesis of new mitochondrial components. While the AMPK targets underlying the first three of these effects are known, a recent paper suggests that direct phosphorylation of the folliculin-interacting protein 1 (FNIP1) by AMPK may be involved in the remaining two.
    Language English
    Publishing date 2023-06-22
    Publishing country England
    Document type Journal Article
    ISSN 2755-0230
    ISSN (online) 2755-0230
    DOI 10.1093/lifemeta/load027
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  5. Article ; Online: AMPK as a direct sensor of long-chain fatty acyl-CoA esters.

    Hardie, D Grahame

    Nature metabolism

    2020  Volume 2, Issue 9, Page(s) 799–800

    Language English
    Publishing date 2020-07-27
    Publishing country Germany
    Document type Journal Article
    ISSN 2522-5812
    ISSN (online) 2522-5812
    DOI 10.1038/s42255-020-0249-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: AMP-activated protein kinase can be allosterically activated by ADP but AMP remains the key activating ligand.

    Hawley, Simon A / Russell, Fiona M / Hardie, D Grahame

    The Biochemical journal

    2024  Volume 481, Issue 8, Page(s) 587–599

    Abstract: The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. When activated by increases in ADP:ATP and/or AMP:ATP ratios (signalling energy deficit), AMPK acts to restore energy balance. Binding of AMP to one or more of three CBS ... ...

    Abstract The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. When activated by increases in ADP:ATP and/or AMP:ATP ratios (signalling energy deficit), AMPK acts to restore energy balance. Binding of AMP to one or more of three CBS repeats (CBS1, CBS3, CBS4) on the AMPK-γ subunit activates the kinase complex by three complementary mechanisms: (i) promoting α-subunit Thr172 phosphorylation by the upstream kinase LKB1; (ii) protecting against Thr172 dephosphorylation; (iii) allosteric activation. Surprisingly, binding of ADP has been reported to mimic the first two effects, but not the third. We now show that at physiologically relevant concentrations of Mg.ATP2- (above those used in the standard assay) ADP binding does cause allosteric activation. However, ADP causes only a modest activation because (unlike AMP), at concentrations just above those where activation becomes evident, ADP starts to cause competitive inhibition at the catalytic site. Our results cast doubt on the physiological relevance of the effects of ADP and suggest that AMP is the primary activator in vivo. We have also made mutations to hydrophobic residues involved in binding adenine nucleotides at each of the three γ subunit CBS repeats of the human α2β2γ1 complex and examined their effects on regulation by AMP and ADP. Mutation of the CBS3 site has the largest effects on all three mechanisms of AMP activation, especially at lower ATP concentrations, while mutation of CBS4 reduces the sensitivity to AMP. All three sites appear to be required for allosteric activation by ADP.
    MeSH term(s) Adenosine Diphosphate/metabolism ; Adenosine Monophosphate/metabolism ; Humans ; Allosteric Regulation ; AMP-Activated Protein Kinases/metabolism ; AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/chemistry ; Ligands ; Phosphorylation ; Adenosine Triphosphate/metabolism ; Enzyme Activation ; Protein Binding
    Chemical Substances Adenosine Diphosphate (61D2G4IYVH) ; Adenosine Monophosphate (415SHH325A) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Ligands ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2024-04-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20240082
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    Uc I Zs.110: Show issues Location:
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  7. Article ; Online: New insights into activation and function of the AMPK.

    Steinberg, Gregory R / Hardie, D Grahame

    Nature reviews. Molecular cell biology

    2022  Volume 24, Issue 4, Page(s) 255–272

    Abstract: The classical role of AMP-activated protein kinase (AMPK) is as a cellular energy sensor activated by falling energy status, signalled by increases in AMP to ATP and ADP to ATP ratios. Once activated, AMPK acts to restore energy homeostasis by promoting ... ...

    Abstract The classical role of AMP-activated protein kinase (AMPK) is as a cellular energy sensor activated by falling energy status, signalled by increases in AMP to ATP and ADP to ATP ratios. Once activated, AMPK acts to restore energy homeostasis by promoting ATP-producing catabolic pathways while inhibiting energy-consuming processes. In this Review, we provide an update on this canonical (AMP/ADP-dependent) activation mechanism, but focus mainly on recently described non-canonical pathways, including those by which AMPK senses the availability of glucose, glycogen or fatty acids and by which it senses damage to lysosomes and nuclear DNA. We also discuss new findings on the regulation of carbohydrate and lipid metabolism, mitochondrial and lysosomal homeostasis, and DNA repair. Finally, we discuss the role of AMPK in cancer, obesity, diabetes, nonalcoholic steatohepatitis (NASH) and other disorders where therapeutic targeting may exert beneficial effects.
    MeSH term(s) AMP-Activated Protein Kinases/metabolism ; Energy Metabolism ; Lipid Metabolism ; Glucose/metabolism ; Adenosine Triphosphate/metabolism
    Chemical Substances AMP-Activated Protein Kinases (EC 2.7.11.31) ; Glucose (IY9XDZ35W2) ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2022-10-31
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2031313-5
    ISSN 1471-0080 ; 1471-0072
    ISSN (online) 1471-0080
    ISSN 1471-0072
    DOI 10.1038/s41580-022-00547-x
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  8. Article ; Online: Targeting an energy sensor to treat diabetes.

    Hardie, D Grahame

    Science (New York, N.Y.)

    2017  Volume 357, Issue 6350, Page(s) 455–456

    MeSH term(s) Blood Glucose ; Diabetes Mellitus ; Humans ; Physical Phenomena
    Chemical Substances Blood Glucose
    Language English
    Publishing date 2017-08-03
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aao1913
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  9. Article ; Online: Keeping the home fires burning: AMP-activated protein kinase.

    Hardie, D Grahame

    Journal of the Royal Society, Interface

    2018  Volume 15, Issue 138

    Abstract: Living cells obtain energy either by oxidizing reduced compounds of organic or mineral origin or by absorbing light. Whichever energy source is used, some of the energy released is conserved by converting adenosine diphosphate (ADP) to adenosine ... ...

    Abstract Living cells obtain energy either by oxidizing reduced compounds of organic or mineral origin or by absorbing light. Whichever energy source is used, some of the energy released is conserved by converting adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which are analogous to the chemicals in a rechargeable battery. The energy released by the conversion of ATP back to ADP is used to drive most energy-requiring processes, including cell growth, cell division, communication and movement. It is clearly essential to life that the production and consumption of ATP are always maintained in balance, and the AMP-activated protein kinase (AMPK) is one of the key cellular regulatory systems that ensures this. In eukaryotic cells (cells with nuclei and other internal membrane-bound structures, including human cells), most ATP is produced in mitochondria, which are thought to have been derived by the engulfment of oxidative bacteria by a host cell not previously able to use molecular oxygen. AMPK is activated by increasing AMP or ADP (AMP being generated from ADP whenever ADP rises) coupled with falling ATP. Relatives of AMPK are found in essentially all eukaryotes, and it may have evolved to allow the host cell to monitor the output of the newly acquired mitochondria and step their ATP production up or down according to the demand. Structural studies have illuminated how AMPK achieves the task of detecting small changes in AMP and ADP, despite the presence of much higher concentrations of ATP. Recently, it has been shown that AMPK can also sense the availability of glucose, the primary carbon source for most eukaryotic cells, via a mechanism independent of changes in AMP or ADP. Once activated by energy imbalance or glucose lack, AMPK modifies many target proteins by transferring phosphate groups to them from ATP. By this means, numerous ATP-producing processes are switched on (including the production of new mitochondria) and ATP-consuming processes are switched off, thus restoring energy homeostasis. Drugs that modulate AMPK have great potential in the treatment of metabolic disorders such as obesity and Type 2 diabetes, and even cancer. Indeed, some existing drugs such as metformin and aspirin, which were derived from traditional herbal remedies, appear to work, in part, by activating AMPK.
    MeSH term(s) AMP-Activated Protein Kinases/metabolism ; Animals ; Cell Line ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Energy Metabolism ; Homeostasis ; Humans ; Mitochondria/metabolism ; Mitochondria/pathology ; Neoplasm Proteins/metabolism ; Neoplasms/metabolism ; Neoplasms/pathology ; Obesity/metabolism ; Obesity/pathology ; Phosphorylation
    Chemical Substances Neoplasm Proteins ; AMP-Activated Protein Kinases (EC 2.7.11.31)
    Language English
    Publishing date 2018-01-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2156283-0
    ISSN 1742-5662 ; 1742-5689
    ISSN (online) 1742-5662
    ISSN 1742-5689
    DOI 10.1098/rsif.2017.0774
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  10. Article ; Online: BAY-3827 and SBI-0206965: Potent AMPK Inhibitors That Paradoxically Increase Thr172 Phosphorylation.

    Hawley, Simon A / Russell, Fiona M / Ross, Fiona A / Hardie, D Grahame

    International journal of molecular sciences

    2023  Volume 25, Issue 1

    Abstract: AMP-activated protein kinase (AMPK) is the central component of a signalling pathway that senses energy stress and triggers a metabolic switch away from anabolic processes and towards catabolic processes. There has been a prolonged focus in the ... ...

    Abstract AMP-activated protein kinase (AMPK) is the central component of a signalling pathway that senses energy stress and triggers a metabolic switch away from anabolic processes and towards catabolic processes. There has been a prolonged focus in the pharmaceutical industry on the development of AMPK-activating drugs for the treatment of metabolic disorders such as Type 2 diabetes and non-alcoholic fatty liver disease. However, recent findings suggest that AMPK inhibitors might be efficacious for treating certain cancers, especially lung adenocarcinomas, in which the
    MeSH term(s) Humans ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; AMP-Activated Protein Kinases ; Diabetes Mellitus, Type 2 ; Lung Neoplasms ; Benzamides ; Pyrimidines
    Chemical Substances SBI-0206965 ; Protein Kinase Inhibitors ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Benzamides ; Pyrimidines
    Language English
    Publishing date 2023-12-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms25010453
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