Glucosylsphingosine affects mitochondrial function in a neuronal cell model
Abstract Gaucher disease arises from mutations in glucocerebrosidase resulting in accumulation of glucosylceramide, which is deacylated to glucosylsphingosine. Mutations in glucocerebrosidase are the greatest known genetic risk factor for Parkinson’s disease. Glucosylsphingosine is a biomarker for G...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08684-7 |
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| _version_ | 1849226009880035328 |
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| author | Valeria Nikolaenko Reddy Vootukuri Simon Eaton Jenny Hällqvist Tomas Baldwin Kevin Mills Wendy Heywood |
| author_facet | Valeria Nikolaenko Reddy Vootukuri Simon Eaton Jenny Hällqvist Tomas Baldwin Kevin Mills Wendy Heywood |
| author_sort | Valeria Nikolaenko |
| collection | DOAJ |
| description | Abstract Gaucher disease arises from mutations in glucocerebrosidase resulting in accumulation of glucosylceramide, which is deacylated to glucosylsphingosine. Mutations in glucocerebrosidase are the greatest known genetic risk factor for Parkinson’s disease. Glucosylsphingosine is a biomarker for Gaucher disease and studies demonstrate its relevance to disease pathology, yet the mechanisms of its toxicity remain little understood. Using proteomics, we show that incubation of SH-Sy5y cells with glucosylsphingosine at physiological plasma concentrations observed in moderate/ severe Gaucher disease negatively effects the TCA cycle, mitochondrial function, glycolysis and protein ubiquitination. Functional analyses confirmed that glucosylsphingosine reduces ATP production, elicits oxidative stress and an increase of glycolysis. Analyses of ubiquitinated proteins and lipid-binding studies demonstrated that glucosylsphingosine has binding affinity for tubulin alpha and induced a specific increase of ubiquitination of α and β tubulins. In conclusion, supranormal levels of glucosylsphingosine affect cellular energy metabolism which may contribute to the pathology in Gaucher disease. |
| format | Article |
| id | doaj-art-afcf1397f1d44e479033e28a11d67bbf |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-afcf1397f1d44e479033e28a11d67bbf2025-08-24T11:46:03ZengNature PortfolioCommunications Biology2399-36422025-08-018111210.1038/s42003-025-08684-7Glucosylsphingosine affects mitochondrial function in a neuronal cell modelValeria Nikolaenko0Reddy Vootukuri1Simon Eaton2Jenny Hällqvist3Tomas Baldwin4Kevin Mills5Wendy Heywood6Translational Mass Spectrometry Research Group, Genetics & Genomic Medicine Dept., UCL Institute of Child HealthTranslational Mass Spectrometry Research Group, Genetics & Genomic Medicine Dept., UCL Institute of Child HealthDevelopmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child HealthTranslational Mass Spectrometry Research Group, Genetics & Genomic Medicine Dept., UCL Institute of Child HealthTranslational Mass Spectrometry Research Group, Genetics & Genomic Medicine Dept., UCL Institute of Child HealthTranslational Mass Spectrometry Research Group, Genetics & Genomic Medicine Dept., UCL Institute of Child HealthTranslational Mass Spectrometry Research Group, Genetics & Genomic Medicine Dept., UCL Institute of Child HealthAbstract Gaucher disease arises from mutations in glucocerebrosidase resulting in accumulation of glucosylceramide, which is deacylated to glucosylsphingosine. Mutations in glucocerebrosidase are the greatest known genetic risk factor for Parkinson’s disease. Glucosylsphingosine is a biomarker for Gaucher disease and studies demonstrate its relevance to disease pathology, yet the mechanisms of its toxicity remain little understood. Using proteomics, we show that incubation of SH-Sy5y cells with glucosylsphingosine at physiological plasma concentrations observed in moderate/ severe Gaucher disease negatively effects the TCA cycle, mitochondrial function, glycolysis and protein ubiquitination. Functional analyses confirmed that glucosylsphingosine reduces ATP production, elicits oxidative stress and an increase of glycolysis. Analyses of ubiquitinated proteins and lipid-binding studies demonstrated that glucosylsphingosine has binding affinity for tubulin alpha and induced a specific increase of ubiquitination of α and β tubulins. In conclusion, supranormal levels of glucosylsphingosine affect cellular energy metabolism which may contribute to the pathology in Gaucher disease.https://doi.org/10.1038/s42003-025-08684-7 |
| spellingShingle | Valeria Nikolaenko Reddy Vootukuri Simon Eaton Jenny Hällqvist Tomas Baldwin Kevin Mills Wendy Heywood Glucosylsphingosine affects mitochondrial function in a neuronal cell model Communications Biology |
| title | Glucosylsphingosine affects mitochondrial function in a neuronal cell model |
| title_full | Glucosylsphingosine affects mitochondrial function in a neuronal cell model |
| title_fullStr | Glucosylsphingosine affects mitochondrial function in a neuronal cell model |
| title_full_unstemmed | Glucosylsphingosine affects mitochondrial function in a neuronal cell model |
| title_short | Glucosylsphingosine affects mitochondrial function in a neuronal cell model |
| title_sort | glucosylsphingosine affects mitochondrial function in a neuronal cell model |
| url | https://doi.org/10.1038/s42003-025-08684-7 |
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