Age-Related Changes in the Glycolytic Enzymes of M2-Isoform of Pyruvate Kinase and Fructose-1,6-Bisphosphate Aldolase: Implications to Age-Related Macular Degeneration DOI Creative Commons
Ammaji Rajala, Raju V. S. Rajala

Aging and Disease, Journal Year: 2024, Volume and Issue: 15(5), P. 2271 - 2271

Published: Jan. 1, 2024

Prior studies have emphasized a bioenergetic crisis in the retinal pigment epithelium (RPE) as critical factor development of age-related macular degeneration (AMD). The isoforms Fructose-1,6-bisphosphate aldolase C (ALDOC) and pyruvate kinase M2 (PKM2) been proposed to play role AMD pathogenesis. While PKM2 ALDOC are crucial for aerobic glycolysis neural retina, they not essential RPE. In this study, we examined expression activity both young aged RPE cells, well retina tissue mice, including an experimentally induced mouse model. Our findings reveal upregulation expression, accompanied by increased activity, Conversely, there is decrease but increase retina. Overall, our study indicates that cells tend favor glycolysis, while tendency diminished These results underscore significance targeting promising therapeutic approach address prevent vision loss AMD.

Language: Английский

Müller cells trophism and pathology as the next therapeutic targets for retinal diseases. DOI Creative Commons
Alessandro Arrigo, Ottavio Cremona, Emanuela Aragona

et al.

Progress in Retinal and Eye Research, Journal Year: 2025, Volume and Issue: unknown, P. 101357 - 101357

Published: April 1, 2025

Language: Английский

Citations

0
Pyruvate and Related Energetic Metabolites Modulate Resilience Against High Genetic Risk for Glaucoma DOI Creative Commons
Keva Li, Nicholas Tolman, Ayellet V. Segrè

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Abstract Glaucoma polygenic risk scores (PRS) effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study the UK Biobank, we investigated whether plasma metabolites enhanced prediction if metabolomic signature of high-genetic existed. Logistic regression models incorporating 168 NMR-based into PRS-based assessments were developed, multiple comparison corrections applied. While weakly predicted (Area Under Curve=0.579), they offered modest improvement PRS-only-based (P=0.004). We identified associated top decile, elevated glycolysis-related metabolites—lactate (P=8.8E-12), pyruvate (P=1.9E-10), citrate (P=0.02)—linked reduced prevalence. These combined significantly modified PRS-glaucoma relationship (P interaction =0.011). Higher total metabolite levels within highest quartile corresponded lower prevalence (Odds Ratio vs. lowest =0.71, 95% Confidence Interval [CI]=0.64–0.80). As is foundational linking glycolysis tricarboxylic acid cycle metabolism ATP generation, pursued experimental validation for putative biomarker human-relevant Mus musculus model. Dietary mitigated intraocular pressure (P=0.002) optic nerve damage (P<0.0003) Lmx1b V265D mice. findings highlight protective role pyruvate-related against suggest potential avenues therapeutic intervention.

Language: Английский

Citations

0
Pyruvate and Related Energetic Metabolites Modulate Resilience Against High Genetic Risk for Glaucoma DOI Open Access
Keva Li, Nicholas Tolman, Ayellet V. Segrè

et al.

Published: March 11, 2025

A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced prediction if metabolomic signature high-genetic-risk existed. Logistic regression models incorporating 168 NMR-based into PRS-based assessments were developed, multiple comparison corrections applied. While weakly predicted (Area Under Curve = 0.579), they offered marginal improvement PRS-only-based (p=0.004). We identified associated top decile, elevated glycolysis-related metabolites-lactate (p=8.8E-12), pyruvate (p=1.9E-10), citrate (p=0.02)-linked reduced prevalence. These combined significantly modified PRS-glaucoma relationship (Pinteraction 0.011). Higher total metabolite levels within highest quartile corresponded lower prevalence (Odds Ratiohighest vs. lowest quartile=0.71, 95% Confidence Interval 0.64-0.80). As is foundational linking glycolysis tricarboxylic acid cycle metabolism ATP generation, pursued experimental validation for putative biomarker human-relevant Mus musculus model. Dietary mitigated intraocular pressure (p=0.002) optic nerve damage (p<0.0003) Lmx1bV265D mice. findings highlight protective role pyruvate-related against suggest potential avenues therapeutic intervention.

Language: Английский

Citations

0
Pyruvate and Related Energetic Metabolites Modulate Resilience Against High Genetic Risk for Glaucoma DOI Open Access
Keva Li, Nicholas Tolman, Ayellet V. Segrè

et al.

Published: March 11, 2025

Glaucoma polygenic risk scores (PRS) effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study the UK Biobank, we investigated whether plasma metabolites enhanced prediction if metabolomic signature of high-genetic existed. Logistic regression models incorporating 168 NMR-based into PRS-based assessments were developed, multiple comparison corrections applied. While weakly predicted (Area Under Curve=0.579), they offered modest improvement PRS-only-based (P=0.004). We identified associated top decile, elevated glycolysis-related metabolites—lactate (P=8.8E-12), pyruvate (P=1.9E-10), citrate (P=0.02)—linked reduced prevalence. These combined significantly modified PRS-glaucoma relationship (P interaction =0.011). Higher total metabolite levels within highest quartile corresponded lower prevalence (Odds Ratio vs. lowest =0.71, 95% Confidence Interval [CI]=0.64–0.80). As is foundational linking glycolysis tricarboxylic acid cycle metabolism ATP generation, pursued experimental validation for putative biomarker human-relevant Mus musculus model. Dietary mitigated intraocular pressure (P=0.002) optic nerve damage (P<0.0003) Lmx1b V265D mice. findings highlight protective role pyruvate-related against suggest potential avenues therapeutic intervention.

Language: Английский

Citations

0
Pyruvate and Related Energetic Metabolites Modulate Resilience Against High Genetic Risk for Glaucoma DOI Open Access
Keva Li, Nicholas Tolman, Ayellet V. Segrè

et al.

Published: March 28, 2025

A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced prediction if metabolomic signature high-genetic-risk existed. Logistic regression models incorporating 168 NMR-based into PRS-based assessments were developed, multiple comparison corrections applied. While weakly predicted (Area Under Curve=0.579), they offered marginal improvement PRS-only-based (P=0.004). We identified associated top decile, elevated glycolysis-related metabolites—lactate (P=8.8E-12), pyruvate (P=1.9E-10), citrate (P=0.02)—linked reduced prevalence. These combined significantly modified PRS-glaucoma relationship (P interaction =0.011). Higher total metabolite levels within highest quartile corresponded lower prevalence (Odds Ratio vs. lowest =0.71, 95% Confidence Interval=0.64–0.80). As is foundational linking glycolysis tricarboxylic acid cycle metabolism ATP generation, pursued experimental validation for putative biomarker human-relevant Mus musculus model. Dietary mitigated intraocular pressure (P=0.002) optic nerve damage (P<0.0003) Lmx1b V265D mice. findings highlight protective role pyruvate-related against suggest potential avenues therapeutic intervention.

Language: Английский

Citations

0
Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma DOI Creative Commons
Keva Li, Nicholas Tolman, Ayellet V. Segrè

et al.

eLife, Journal Year: 2025, Volume and Issue: 14

Published: April 24, 2025

A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced prediction if metabolomic signature high-genetic-risk existed. Logistic regression models incorporating 168 NMR-based into PRS-based assessments were developed, multiple comparison corrections applied. While weakly predicted (Area Under Curve = 0.579), they offered marginal improvement PRS-only-based (p=0.004). We identified associated top decile, elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), citrate (p=0.02)—linked reduced prevalence. These combined significantly modified PRS-glaucoma relationship (P interaction 0.011). Higher total metabolite levels within highest quartile corresponded lower prevalence (Odds Ratio vs. lowest =0.71, 95% Confidence Interval 0.64–0.80). As is foundational linking glycolysis tricarboxylic acid cycle metabolism ATP generation, pursued experimental validation for putative biomarker human-relevant Mus musculus model. Dietary mitigated intraocular pressure (p=0.002) optic nerve damage (p<0.0003) Lmx1b V265D mice. findings highlight protective role pyruvate-related against suggest potential avenues therapeutic intervention.

Language: Английский

Citations

0
Age-Related Changes in the Glycolytic Enzymes of M2-Isoform of Pyruvate Kinase and Fructose-1,6-Bisphosphate Aldolase: Implications to Age-Related Macular Degeneration DOI Creative Commons
Ammaji Rajala, Raju V. S. Rajala

Aging and Disease, Journal Year: 2024, Volume and Issue: 15(5), P. 2271 - 2271

Published: Jan. 1, 2024

Prior studies have emphasized a bioenergetic crisis in the retinal pigment epithelium (RPE) as critical factor development of age-related macular degeneration (AMD). The isoforms Fructose-1,6-bisphosphate aldolase C (ALDOC) and pyruvate kinase M2 (PKM2) been proposed to play role AMD pathogenesis. While PKM2 ALDOC are crucial for aerobic glycolysis neural retina, they not essential RPE. In this study, we examined expression activity both young aged RPE cells, well retina tissue mice, including an experimentally induced mouse model. Our findings reveal upregulation expression, accompanied by increased activity, Conversely, there is decrease but increase retina. Overall, our study indicates that cells tend favor glycolysis, while tendency diminished These results underscore significance targeting promising therapeutic approach address prevent vision loss AMD.

Language: Английский

Citations

3