Abstract
Evidence suggests that metabolic dysregulation plays an important role in disease etiology of retinal degenerations. Several studies suggest that preserving the retinal metabolic ecosystem may be protective against retinal degenerations. We investigated whether activation of 5′ adenosine monophosphate protein kinase (AMPK) is protective to the retina in several preclinical mouse models of retinal degeneration and found that metformin-induced activation of AMPK was able to delay or prevent retinal degeneration in the rd10 model of retinitis pigmentosa, the NaIO3 model of RPE and retinal injury, and the light damage model of retinal degeneration. This protection was associated with increased mitochondrial DNA copy number, increased levels of ATP, and a reduction in oxidative stress and oxidative DNA damage. We propose that AMPK plays an important role in regulation of the retinal metabolic ecosystem and that activation of AMPK may promote metabolic processes to prevent retinal degeneration.
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References
Ait-Ali N, Fridlich R, Millet-Puel G, Clerin E, Delalande F, Jaillard C, Blond F, Perrocheau L, Reichman S, Byrne LC, Olivier-Bandini A, Bellalou J, Moyse E, Bouillaud F, Nicol X, Dalkara D, van Dorsselaer A, Sahel JA, Leveillard T (2015) Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis. Cell (United States) 161:817–832
Calabrese MF et al (2014) Structural basis for AMPK activation: natural and synthetic ligands regulate kinase activity from opposite poles by different molecular mechanisms. Structure (United States) 22:1161–1172
Du J, Rountree A, Cleghorn WM, Contreras L, Lindsay KJ, Sadilek M, Gu H, Djukovic D, Raftery D, Satrustegui J, Kanow M, Chan L, Tsang SH, Sweet IR, Hurley JB (2016) Phototransduction influences metabolic flux and nucleotide metabolism in mouse retina. J Biol Chem (United States) 291:4698–4710
Gowans GJ, Hawley SA, Ross FA, Hardie DG (2013) AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab (United States) 18:556–566
Hurley JB, Lindsay KJ, Du J (2015) Glucose, lactate, and shuttling of metabolites in vertebrate retinas. J Neurosci Res (United States) 93:1079–1092
Kanow MA, Giarmarco MM, Jankowski CS, Tsantilas K, Engel AL, Du J, Linton JD, Farnsworth CC, Sloat SR, Rountree A, Sweet IR, Lindsay KJ, Parker ED, Brockerhoff SE, Sadilek M, Chao JR, Hurley JB (2017) Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye. Elife (England) 6. https://doi.org/10.7554/eLife.28899
Krebs H (1927) On the metabolism of the retina. Biochem Z 189:57–58, 59.
Lin HC, Stein JD, Nan B, Childers D, Newman-Casey PA, Thompson DA, Richards JE (2015) Association of geroprotective effects of metformin and risk of open-angle glaucoma in persons with diabetes mellitus. JAMA Ophthalmol (United States) 133:915–923
Lindsay KJ, Du J, Sloat SR, Contreras L, Linton JD, Turner SJ, Sadilek M, Satrustegui J, Hurley JB (2014) Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina. Proc Natl Acad Sci U S A (United States) 111:15579–15584
Ma S, Venkatesh A, Langellotto F, Le YZ, Hall MN, Ruegg MA, Punzo C (2015) Loss of mTOR signaling affects cone function, cone structure and expression of cone specific proteins without affecting cone survival. Exp Eye Res (England) 135:1–13
Maleskic S, Kusturica J, Gusic E, Rakanovic-Todic M, Secic D, Burnazovic-Ristic L, Kulo A (2017) Metformin use associated with protective effects for ocular complications in patients with type 2 diabetes - observational study. Acta Med Acad (Bosnia and Herzegovina) 46:116–123
Punzo C, Kornacker K, Cepko CL (2009) Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci (United States) 12:44–52
Samuel MA, Voinescu PE, Lilley BN, de Cabo R, Foretz M, Viollet B, Pawlyk B, Sandberg MA, Vavvas DG, Sanes JR (2014) LKB1 and AMPK regulate synaptic remodeling in old age. Nat Neurosci (United States) 17:1190–1197
Venkatesh A, Ma S, Le YZ, Hall MN, Ruegg MA, Punzo C (2015) Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice. J Clin Invest (United States) 125:1446–1458
Villena JE, Yoshiyama CA, Sanchez JE, Hilario NL, Merin LM (2011) Prevalence of diabetic retinopathy in peruvian patients with type 2 diabetes: results of a hospital-based retinal telescreening program. Rev Panam Salud Publica (United States) 30:408–414
Wahlqvist ML, Lee MS, Hsu CC, Chuang SY, Lee JT, Tsai HN (2012) Metformin-inclusive sulfonylurea therapy reduces the risk of parkinson's disease occurring with type 2 diabetes in a taiwanese population cohort. Parkinsonism Relat Disord (England) 18:753–758
Warburg O, Posener K, Negrelein E (1924) On the metabolism of carcinoma cells. Bioschemische Zeitschrift 152:309–344
Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, Walker PA, Haire L, Eccleston JF, Davis CT, Martin SR, Carling D, Gamblin SJ (2007) Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature (England) 449:496–500
Xu L, Kong L, Wang J, Ash JD (2018) Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium. Proc Natl Acad Sci U S A (United States) 115:10475–10480
Zhang L, Du J, Justus S, Hsu CW, Bonet-Ponce L, Wu WH, Tsai YT, Wu WP, Jia Y, Duong JK, Mahajan VB, Lin CS, Wang S, Hurley JB, Tsang SH (2016) Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration. J Clin Invest (United States) 126:4659–4673
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Brown, E.E., Lewin, A.S., Ash, J.D. (2019). AMPK May Play an Important Role in the Retinal Metabolic Ecosystem. In: Bowes Rickman, C., Grimm, C., Anderson, R., Ash, J., LaVail, M., Hollyfield, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 1185. Springer, Cham. https://doi.org/10.1007/978-3-030-27378-1_78
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DOI: https://doi.org/10.1007/978-3-030-27378-1_78
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