Abstract
Adenosine monophosphate-activated kinase (AMPK) is a highly conserved protein kinase found in all eukaryotic genomes. It exists as heterotrimeric protein consisting of α, β, and γ subunits. AMPK is activated by elevated levels of adenosine mono-phosphate (AMP), which is produced during conditions of low ATP production and perhaps mitochondrial dysfunction. Activation of AMPK has been shown to regulate a large number of downstream pathways. These will either increase energy production such as increase oxidation of fatty acids and glucose, or decrease energy utilization such as inhibiting synthesis of glycogen, fatty acid synthesis, and protein synthesis. In addition, being a key regulator of physiological energy dynamics, AMPK has been demonstrated to play roles in regulating various cellular processes such as mitochondrial biogenesis (Jager et al. Proc Natl Acad Sci U S A 104:12017–12022, 2007), autophagy (Hyttinen et al. Rejuven Res 14:651–660, 2011) and inflammation and immune responses (Giri et al. 2004). Retinal neurons have a high energy demand but have a poor energy storage capacity. Because of this, it is likely that the AMPK signaling pathway plays an important role in maintaining energy balance, and therefore may be a therapeutic target to prevent or delay retinal degeneration.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
Abbreviations
- AMPK:
-
Adenosine monophosphate protein activated kinase
- CaMKK IIβ:
-
Calmodulin-dependent protein kinase kinase IIβ
- TAK1:
-
Mammalian transforming growth factor β-activated kinase
- AMP:
-
Adenosine monophosphate
- ADP:
-
Adenosine diphosphate
- PGC-1:
-
Peroxisome proliferator-activated receptor-γ co-activator
- AICAR:
-
5-aminoimidazole-4-carboxamide ribonucleoside
- mTOR:
-
Mammalian target of rapamycin
- ICAM1:
-
Intercellular adhesion molecule 1
- 4E-BP1:
-
Eukaryotic translation initiation factor 4E-binding protein 1
Reference
Ai D, Jiang H, Westerterp M et al (2014) Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis. Circ Res 114:1576–1584
Barot M, Gokulgandhi MR, Mitra AK (2011) Mitochondrial dysfunction in retinal diseases. Curr Eye Res 36:1069–1077
Bove J, Martinez-Vicente M, Vila M (2011) Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci 12:437–452
Egger A, Samardzija M, Sothilingam V et al (2012) PGC-1alpha determines light damage susceptibility of the murine retina. PLoS One 7:e31272
El-Mir MY, Detaille D, G RV et al (2008) Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci 34:77–87
Giri S, Nath N, Smith B et al (2004) 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J Neurosci 24:479–487
Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C et al (2009) TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J 28:677–685
Hyttinen JM, Petrovski G, Salminen A et al (2011) 5′-Adenosine monophosphate-activated protein kinase—mammalian target of rapamycin axis as therapeutic target for age-related macular degeneration. Rejuven Res 14:651–660
Inoki K, Kim J, Guan KL (2012) AMPK and mTOR in cellular energy homeostasis and drug targets. Ann Rev Pharm Toxicol 52:381–400
Jager S, Handschin C, St-Pierre J et al (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 104:12017–12022
Jiang T, Yu JT, Zhu XC et al (2014) Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br J Pharmacol 171:3146–3157
Jiang T, Yu JT, Zhu XC et al (2015) Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke. Mol Neurobiol. 51(1):220–229
Kaarniranta K, Kauppinen A, Blasiak J et al (2012) Autophagy regulating kinases as potential therapeutic targets for age-related macular degeneration. Future Med Chem 4:2153–2161
Kamoshita M, Ozawa Y, Kubota S et al (2014) AMPK-NF-kappaB axis in the photoreceptor disorder during retinal inflammation. PLoS One 9:e103013
Kim J, Kundu M, Viollet B et al (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141
Kubota S, Ozawa Y, Kurihara T et al (2011) Roles of AMP-activated protein kinase in diabetes-induced retinal inflammation. Invest Ophthalmol Vis Sci 52:9142–9148
Lee S, Van Bergen NJ, Kong GY et al (2011) Mitochondrial dysfunction in glaucoma and emerging bioenergetic therapies. Exp Eye Res 93:204–212
Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370
Nagai N, Kubota S, Tsubota K et al (2014) Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types. J Nutr Biochem 25:1218–1225
O’Neill LA, Hardie DG (2013) Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493:346–355
O’Neill HM, Maarbjerg SJ, Crane JD et al (2011) AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc Natl Acad Sci U S A 108:16092–16097
Qin S, De Vries GW (2008) alpha2 but not alpha1 AMP-activated protein kinase mediates oxidative stress-induced inhibition of retinal pigment epithelium cell phagocytosis of photoreceptor outer segments. J Biol Chem 283:6744–6751
Qin S, Rodrigues GA (2010) Differential roles of AMPKalpha1 and AMPKalpha2 in regulating 4-HNE-induced RPE cell death and permeability. Exp Eye Res 91:818–824
Santos JM, Tewari S, Goldberg AF et al (2011) Mitochondrial biogenesis and the development of diabetic retinopathy. Free Rad Biol Med 51:1849–1860
Viollet B, Foretz M, Guigas B et al (2006) Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J Phys 574:41–53
Viollet B, Athea Y, Mounier R et al (2009) AMPK: lessons from transgenic and knockout animals. Front Biosci (Landmark Ed) 14:19–44
Wu SB, Wu YT, Wu TP et al (2014) Role of AMPK-mediated adaptive responses in human cells with mitochondrial dysfunction to oxidative stress. Biochim Biophys Acta 1840:1331–1344
Zhao C, Yasumura D, Li X et al (2011) mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest 121:369–383
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this paper
Cite this paper
Xu, L., Ash, J. (2016). The Role of AMPK Pathway in Neuroprotection. In: Bowes Rickman, C., LaVail, M., Anderson, R., Grimm, C., Hollyfield, J., Ash, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 854. Springer, Cham. https://doi.org/10.1007/978-3-319-17121-0_56
Download citation
DOI: https://doi.org/10.1007/978-3-319-17121-0_56
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-17120-3
Online ISBN: 978-3-319-17121-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)