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Metabolic Alterations Caused by Simultaneous Loss of HK2 and PKM2 Leads to Photoreceptor Dysfunction and Degeneration

HK2 and PKM2 are two main regulators of aerobic glycolysis. Photoreceptors (PRs) use aerobic glycolysis to produce the biomass necessary for the daily renewal of their outer segments. Previous work has shown that HK2 and PKM2 are important for the normal function and long-term survival of PRs but ar...

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Autores principales: Weh, Eric, Goswami, Moloy, Chaudhury, Sraboni, Fernando, Roshini, Miller, Nick, Hager, Heather, Sheskey, Sarah, Sharma, Vikram, Wubben, Thomas J., Besirli, Cagri G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10453858/
https://www.ncbi.nlm.nih.gov/pubmed/37626853
http://dx.doi.org/10.3390/cells12162043
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author Weh, Eric
Goswami, Moloy
Chaudhury, Sraboni
Fernando, Roshini
Miller, Nick
Hager, Heather
Sheskey, Sarah
Sharma, Vikram
Wubben, Thomas J.
Besirli, Cagri G.
author_facet Weh, Eric
Goswami, Moloy
Chaudhury, Sraboni
Fernando, Roshini
Miller, Nick
Hager, Heather
Sheskey, Sarah
Sharma, Vikram
Wubben, Thomas J.
Besirli, Cagri G.
author_sort Weh, Eric
collection PubMed
description HK2 and PKM2 are two main regulators of aerobic glycolysis. Photoreceptors (PRs) use aerobic glycolysis to produce the biomass necessary for the daily renewal of their outer segments. Previous work has shown that HK2 and PKM2 are important for the normal function and long-term survival of PRs but are dispensable for PR maturation, and their individual loss has opposing effects on PR survival during acute nutrient deprivation. We generated double conditional (dcKO) mice lacking HK2 and PKM2 expression in rod PRs. Western blotting, immunofluorescence, optical coherence tomography, and electroretinography were used to characterize the phenotype of dcKO animals. Targeted and stable isotope tracing metabolomics, qRT-PCR, and retinal oxygen consumption were performed. We show that dcKO animals displayed early shortening of PR inner/outer segments, followed by loss of PRs with aging, much more rapidly than either knockout alone without functional loss as measured by ERG. Significant alterations to central glucose metabolism were observed without any apparent changes to mitochondrial function, prior to PR degeneration. Finally, PR survival following experimental retinal detachment was unchanged in dcKO animals as compared to wild-type animals. These data suggest that HK2 and PKM2 have differing roles in promoting PR neuroprotection and identifying them has important implications for developing therapeutic options for combating PR loss during retinal disease.
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spelling pubmed-104538582023-08-26 Metabolic Alterations Caused by Simultaneous Loss of HK2 and PKM2 Leads to Photoreceptor Dysfunction and Degeneration Weh, Eric Goswami, Moloy Chaudhury, Sraboni Fernando, Roshini Miller, Nick Hager, Heather Sheskey, Sarah Sharma, Vikram Wubben, Thomas J. Besirli, Cagri G. Cells Article HK2 and PKM2 are two main regulators of aerobic glycolysis. Photoreceptors (PRs) use aerobic glycolysis to produce the biomass necessary for the daily renewal of their outer segments. Previous work has shown that HK2 and PKM2 are important for the normal function and long-term survival of PRs but are dispensable for PR maturation, and their individual loss has opposing effects on PR survival during acute nutrient deprivation. We generated double conditional (dcKO) mice lacking HK2 and PKM2 expression in rod PRs. Western blotting, immunofluorescence, optical coherence tomography, and electroretinography were used to characterize the phenotype of dcKO animals. Targeted and stable isotope tracing metabolomics, qRT-PCR, and retinal oxygen consumption were performed. We show that dcKO animals displayed early shortening of PR inner/outer segments, followed by loss of PRs with aging, much more rapidly than either knockout alone without functional loss as measured by ERG. Significant alterations to central glucose metabolism were observed without any apparent changes to mitochondrial function, prior to PR degeneration. Finally, PR survival following experimental retinal detachment was unchanged in dcKO animals as compared to wild-type animals. These data suggest that HK2 and PKM2 have differing roles in promoting PR neuroprotection and identifying them has important implications for developing therapeutic options for combating PR loss during retinal disease. MDPI 2023-08-10 /pmc/articles/PMC10453858/ /pubmed/37626853 http://dx.doi.org/10.3390/cells12162043 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Weh, Eric
Goswami, Moloy
Chaudhury, Sraboni
Fernando, Roshini
Miller, Nick
Hager, Heather
Sheskey, Sarah
Sharma, Vikram
Wubben, Thomas J.
Besirli, Cagri G.
Metabolic Alterations Caused by Simultaneous Loss of HK2 and PKM2 Leads to Photoreceptor Dysfunction and Degeneration
title Metabolic Alterations Caused by Simultaneous Loss of HK2 and PKM2 Leads to Photoreceptor Dysfunction and Degeneration
title_full Metabolic Alterations Caused by Simultaneous Loss of HK2 and PKM2 Leads to Photoreceptor Dysfunction and Degeneration
title_fullStr Metabolic Alterations Caused by Simultaneous Loss of HK2 and PKM2 Leads to Photoreceptor Dysfunction and Degeneration
title_full_unstemmed Metabolic Alterations Caused by Simultaneous Loss of HK2 and PKM2 Leads to Photoreceptor Dysfunction and Degeneration
title_short Metabolic Alterations Caused by Simultaneous Loss of HK2 and PKM2 Leads to Photoreceptor Dysfunction and Degeneration
title_sort metabolic alterations caused by simultaneous loss of hk2 and pkm2 leads to photoreceptor dysfunction and degeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10453858/
https://www.ncbi.nlm.nih.gov/pubmed/37626853
http://dx.doi.org/10.3390/cells12162043
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