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Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis

Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve photoreceptor survival. Similar to cancer cells, photoreceptors maintain pyruvate kinase muscle isoform 2 (PKM2) expression, which is a critic...

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Autores principales: Wubben, Thomas J., Pawar, Mercy, Weh, Eric, Smith, Andrew, Sajjakulnukit, Peter, Zhang, Li, Dai, Lipeng, Hager, Heather, Pai, Manjunath P., Lyssiotis, Costas A., Besirli, Cagri G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031539/
https://www.ncbi.nlm.nih.gov/pubmed/32076076
http://dx.doi.org/10.1038/s41598-020-59999-w
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author Wubben, Thomas J.
Pawar, Mercy
Weh, Eric
Smith, Andrew
Sajjakulnukit, Peter
Zhang, Li
Dai, Lipeng
Hager, Heather
Pai, Manjunath P.
Lyssiotis, Costas A.
Besirli, Cagri G.
author_facet Wubben, Thomas J.
Pawar, Mercy
Weh, Eric
Smith, Andrew
Sajjakulnukit, Peter
Zhang, Li
Dai, Lipeng
Hager, Heather
Pai, Manjunath P.
Lyssiotis, Costas A.
Besirli, Cagri G.
author_sort Wubben, Thomas J.
collection PubMed
description Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve photoreceptor survival. Similar to cancer cells, photoreceptors maintain pyruvate kinase muscle isoform 2 (PKM2) expression, which is a critical regulator in aerobic glycolysis. Unlike PKM1, which has constitutively high catalytic activity, PKM2 is under complex regulation. Recently, we demonstrated that genetically reprogramming photoreceptor metabolism via PKM2-to-PKM1 substitution is a promising neuroprotective strategy. Here, we explored the neuroprotective effects of pharmacologically activating PKM2 via ML-265, a small molecule activator of PKM2, during acute outer retinal stress. We found that ML-265 increased PKM2 activity in 661 W cells and in vivo in rat eyes without affecting the expression of genes involved in glucose metabolism. ML-265 treatment did, however, alter metabolic intermediates of glucose metabolism and those necessary for biosynthesis in cultured cells. Long-term exposure to ML-265 did not result in decreased photoreceptor function or survival under baseline conditions. Notably, though, ML-265-treatment did reduce entrance into the apoptotic cascade in in vitro and in vivo models of outer retinal stress. These data suggest that reprogramming metabolism via activation of PKM2 is a novel, and promising, therapeutic strategy for photoreceptor neuroprotection.
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spelling pubmed-70315392020-02-27 Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis Wubben, Thomas J. Pawar, Mercy Weh, Eric Smith, Andrew Sajjakulnukit, Peter Zhang, Li Dai, Lipeng Hager, Heather Pai, Manjunath P. Lyssiotis, Costas A. Besirli, Cagri G. Sci Rep Article Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve photoreceptor survival. Similar to cancer cells, photoreceptors maintain pyruvate kinase muscle isoform 2 (PKM2) expression, which is a critical regulator in aerobic glycolysis. Unlike PKM1, which has constitutively high catalytic activity, PKM2 is under complex regulation. Recently, we demonstrated that genetically reprogramming photoreceptor metabolism via PKM2-to-PKM1 substitution is a promising neuroprotective strategy. Here, we explored the neuroprotective effects of pharmacologically activating PKM2 via ML-265, a small molecule activator of PKM2, during acute outer retinal stress. We found that ML-265 increased PKM2 activity in 661 W cells and in vivo in rat eyes without affecting the expression of genes involved in glucose metabolism. ML-265 treatment did, however, alter metabolic intermediates of glucose metabolism and those necessary for biosynthesis in cultured cells. Long-term exposure to ML-265 did not result in decreased photoreceptor function or survival under baseline conditions. Notably, though, ML-265-treatment did reduce entrance into the apoptotic cascade in in vitro and in vivo models of outer retinal stress. These data suggest that reprogramming metabolism via activation of PKM2 is a novel, and promising, therapeutic strategy for photoreceptor neuroprotection. Nature Publishing Group UK 2020-02-19 /pmc/articles/PMC7031539/ /pubmed/32076076 http://dx.doi.org/10.1038/s41598-020-59999-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wubben, Thomas J.
Pawar, Mercy
Weh, Eric
Smith, Andrew
Sajjakulnukit, Peter
Zhang, Li
Dai, Lipeng
Hager, Heather
Pai, Manjunath P.
Lyssiotis, Costas A.
Besirli, Cagri G.
Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis
title Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis
title_full Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis
title_fullStr Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis
title_full_unstemmed Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis
title_short Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis
title_sort small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, pkm2, circumvents photoreceptor apoptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031539/
https://www.ncbi.nlm.nih.gov/pubmed/32076076
http://dx.doi.org/10.1038/s41598-020-59999-w
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