Targeting an energy sensor to treat diabetes

Hardie, D. Grahame

doi:10.1126/science.aao1913

Cited by 22 publications

(14 citation statements)

References 15 publications

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“…To characterize the putative regulation of AMPK activity by redox signals we used differentiated C2C12 mouse myotubes, a model of skeletal muscle fibers in which AMPK is a key regulator of mitochondrial and cellular function ( 11 , 32 , 33 ) ( Fig. S1 A ).…”

Section: Resultsmentioning

confidence: 99%

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Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly

Hinchy

Gruszczyk

Willows

et al. 2018

Journal of Biological Chemistry

233

129

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Mitochondrial reactive oxygen species (ROS) production is a tightly regulated redox signal that transmits information from the organelle to the cell. Other mitochondrial signals, such as ATP, are sensed by enzymes, including the key metabolic sensor and regulator, AMP-activated protein kinase (AMPK). AMPK responds to the cellular ATP/AMP and ATP/ADP ratios by matching mitochondrial ATP production to demand. Previous reports proposed that AMPK activity also responds to ROS, by ROS acting on redox-sensitive cysteine residues (Cys-299/Cys-304) on the AMPK α subunit. This suggests an appealing model in which mitochondria fine-tune AMPK activity by both adenine nucleotide–dependent mechanisms and by redox signals. Here we assessed whether physiological levels of ROS directly alter AMPK activity. To this end we added exogenous hydrogen peroxide (H2O2) to cells and utilized the mitochondria-targeted redox cycler MitoParaquat to generate ROS within mitochondria without disrupting oxidative phosphorylation. Mitochondrial and cytosolic thiol oxidation was assessed by measuring peroxiredoxin dimerization and by redox-sensitive fluorescent proteins. Replacing the putative redox-active cysteine residues on AMPK α1 with alanines did not alter the response of AMPK to H2O2. In parallel with measurements of AMPK activity, we measured the cell ATP/ADP ratio. This allowed us to separate the effects on AMPK activity due to ROS production from those caused by changes in this ratio. We conclude that AMPK activity in response to redox changes is not due to direct action on AMPK itself, but is a secondary consequence of redox effects on other processes, such as mitochondrial ATP production.

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Section: Resultsmentioning

confidence: 99%

“…AMPK can also be activated by atypical mechanisms, independently of changes in the cell's ATP/ADP or ATP/AMP ratio (hereafter AMP-independent regulation) ( 6 – 11 ) ( Fig. 1 A ).…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly

Hinchy

Gruszczyk

Willows

et al. 2018

Journal of Biological Chemistry

233

129

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“…Whilst AMPK clearly emerged as such a key regulator, it is unlikely to be exploitable as a target for anti-leakage treatments: its central role in regulating cellular energy demands throughout the body hints at many potential side effects. Activation of AMPK is currently investigated as a therapeutic option to treat cancer, metabolic syndrome and diabetes 50, 51 . However, in light of the strong induction of permeability we observed in response to at least two AMPK agonists, we propose that these avenues should be explored cautiously, since at least acute microvascular leakage may accompany such treatment modalities.…”

Section: Discussionmentioning

confidence: 99%

AMP-activated protein kinase is a key regulator of acute neurovascular permeability

Dragoni

Caridi

Karatsai

et al. 2019

Preprint

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12Pathological hyperpermeability accompanies many blinding retinopathies. Despite 13 important therapeutic breakthroughs benefitting many but not all retinopathy patients, 14 the intracellular signalling underlying retinal leakage is still poorly understood. We 15 have developed an ex-vivo model, which allowed us to measure and manipulate acute 16 vascular permeability in the intact rodent retina, and combined measurements with 17 immunohistochemical analyses of signal transduction. This ex-vivo retina platform 18 proved to be an easily accessible and reliable tool for systematic identification of 19 regulators of vascular permeability through small molecule antagonists/agonists and 20 siRNA. By using this model, we showed that AMPK was a key mediator of VEGF-and 21 bradykinin-induced permeability by acting downstream of Ca 2+ and CAMKK, and 22 upstream of eNOS/VE-cadherin as well as p38/HSP27. Accordingly, AMPK agonist 23 potently induced retinal vascular leakage, a finding of major importance for their use 24 as therapeutic agents in the treatment of e.g. cancer or metabolic syndrome. 25 26 489 490 1 Nagy, 500 5 Ford, J. A. et al. Current treatments in diabetic macular oedema: systematic review and meta-501 analysis. BMJ Open 3, 504 7 Canning, P. et al. Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target 505 to prevent retinal vasopermeability during diabetes. of phospholipase C, protein 510 kinase C, and calcium in VEGF-induced venular hyperpermeability. Am J Physiol 276, H535-511 542,

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“…Collectively, this increases oxidative phosphorylation, autophagy, and uptake and metabolism of glucose and fatty acids, and decreases the synthesis of fatty acids, cholesterol, proteins, and ribosomal RNAs (rRNAs), as well as decreasing cell growth and proliferation [ 1 , 2 , 3 , 4 , 5 , 6 ]. Due to its central roles in metabolism, AMPK is dysregulated in diabetes, obesity, cardiometabolic disease, and cancer, and it is a promising pharmacological target [ 1 , 2 , 5 , 7 , 8 , 9 , 10 ], especially for the treatment of type 2 diabetes [ 11 , 12 , 13 ].…”

Section: Ampk Is a Master Regulator Of Energy Homeostasis That Is mentioning

confidence: 99%

Structure and Physiological Regulation of AMPK

Yan

Zhou

et al. 2018

IJMS

172

124

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Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric αβγ complex that functions as a central regulator of energy homeostasis. Energy stress manifests as a drop in the ratio of adenosine triphosphate (ATP) to AMP/ADP, which activates AMPK’s kinase activity, allowing it to upregulate ATP-generating catabolic pathways and to reduce energy-consuming catabolic pathways and cellular programs. AMPK senses the cellular energy state by competitive binding of the three adenine nucleotides AMP, ADP, and ATP to three sites in its γ subunit, each, which in turn modulates the activity of AMPK’s kinase domain in its α subunit. Our current understanding of adenine nucleotide binding and the mechanisms by which differential adenine nucleotide occupancies activate or inhibit AMPK activity has been largely informed by crystal structures of AMPK in different activity states. Here we provide an overview of AMPK structures, and how these structures, in combination with biochemical, biophysical, and mutational analyses provide insights into the mechanisms of adenine nucleotide binding and AMPK activity modulation.

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Targeting an energy sensor to treat diabetes

Cited by 22 publications

References 15 publications

Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly

Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly

AMP-activated protein kinase is a key regulator of acute neurovascular permeability

Structure and Physiological Regulation of AMPK

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