Methylglyoxal-induced RNA modifications decrease RNA stability and translation and are associated with type 2 diabetes
Objectives: Methylglyoxal (MG), a reactive aldehyde generated as a byproduct of glucose and lipid metabolism, is known to modify nucleic acids and proteins, altering their structure and function. While MG-induced DNA and protein adducts have been extensively studied and associated with type 2 diabet...
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| Language: | English |
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Elsevier
2025-08-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000936 |
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| author | Edwin De Jesus Lopez Gonzalez SWT Lai Kelani Sun Caree R. Carson Carlos Hernandez-Castillo Tala Zoukari Kassandra Lopez Jianying Zhang Thomas Blevins John Termini Sarah C. Shuck |
| author_facet | Edwin De Jesus Lopez Gonzalez SWT Lai Kelani Sun Caree R. Carson Carlos Hernandez-Castillo Tala Zoukari Kassandra Lopez Jianying Zhang Thomas Blevins John Termini Sarah C. Shuck |
| author_sort | Edwin De Jesus Lopez Gonzalez |
| collection | DOAJ |
| description | Objectives: Methylglyoxal (MG), a reactive aldehyde generated as a byproduct of glucose and lipid metabolism, is known to modify nucleic acids and proteins, altering their structure and function. While MG-induced DNA and protein adducts have been extensively studied and associated with type 2 diabetes (T2D) and its complications, the formation, biological relevance, and functional consequences of MG-induced RNA adducts remain poorly understood. This study aimed to define the chemical structures of MG-derived RNA adducts, assess their presence in clinical samples, and determine their impact on RNA stability and translation. Methods: We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS), nuclear magnetic resonance (NMR), and other spectroscopic techniques to characterize MG-induced RNA adducts formed in vitro and in biological samples. RNA was isolated from cultured cells and clinical urine specimens from individuals with and without T2D. RNA stability and translation were assessed using firefly luciferase reporter mRNAs modified with MG in cell-based assays. Results: In vitro MG treatment resulted in the formation of an unstable product, tentatively identified as N2-(1,2-dihydroxy-2-methyl)ethano-guanosine (cMG-guanosine), and two stable adducts: N2-(1-carboxyethyl)-guanosine (CEG) and N2-(1-carboxyethyl)-7–1-hydroxy-2-oxopropyl-guanosine (MG-CEG). In cellular RNA and urine from patients, only the stereoisomers of CEG were detected. CEG levels were significantly elevated in patients with T2D compared to controls and showed a stronger association with T2D than the DNA adduct N2-(1-carboxyethyl)-deoxyguanosine (CEdG). Furthermore, CEG levels were higher in T2D patients who had developed complications compared to those without complications. Functionally, MG-modified luciferase mRNA exhibited decreased stability and reduced translational efficiency relative to unmodified mRNA. Conclusions: This study provides the first structural and functional characterization of MG-induced RNA adducts and demonstrates their accumulation in individuals with T2D, particularly in those with disease complications. These findings highlight RNA MG-adducts as clinically relevant epitranscriptomic modifications that may contribute to RNA destabilization and impaired translation, suggesting a novel molecular mechanism by which metabolic stress may exacerbate disease progression. |
| format | Article |
| id | doaj-art-4a77ebb8fc0444d881868798053c1ffb |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-4a77ebb8fc0444d881868798053c1ffb2025-08-20T03:28:14ZengElsevierMolecular Metabolism2212-87782025-08-019810218610.1016/j.molmet.2025.102186Methylglyoxal-induced RNA modifications decrease RNA stability and translation and are associated with type 2 diabetesEdwin De Jesus Lopez Gonzalez0SWT Lai1Kelani Sun2Caree R. Carson3Carlos Hernandez-Castillo4Tala Zoukari5Kassandra Lopez6Jianying Zhang7Thomas Blevins8John Termini9Sarah C. Shuck10Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United StatesDepartment of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United StatesDepartment of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United StatesDepartment of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United StatesDepartment of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United StatesDepartment of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United StatesDepartment of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United StatesDepartment of Biostatistics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United StatesTexas Diabetes and Endocrinology, Austin, TX, 78731, United StatesDepartment of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States; Corresponding author.Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States; Corresponding author.Objectives: Methylglyoxal (MG), a reactive aldehyde generated as a byproduct of glucose and lipid metabolism, is known to modify nucleic acids and proteins, altering their structure and function. While MG-induced DNA and protein adducts have been extensively studied and associated with type 2 diabetes (T2D) and its complications, the formation, biological relevance, and functional consequences of MG-induced RNA adducts remain poorly understood. This study aimed to define the chemical structures of MG-derived RNA adducts, assess their presence in clinical samples, and determine their impact on RNA stability and translation. Methods: We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS), nuclear magnetic resonance (NMR), and other spectroscopic techniques to characterize MG-induced RNA adducts formed in vitro and in biological samples. RNA was isolated from cultured cells and clinical urine specimens from individuals with and without T2D. RNA stability and translation were assessed using firefly luciferase reporter mRNAs modified with MG in cell-based assays. Results: In vitro MG treatment resulted in the formation of an unstable product, tentatively identified as N2-(1,2-dihydroxy-2-methyl)ethano-guanosine (cMG-guanosine), and two stable adducts: N2-(1-carboxyethyl)-guanosine (CEG) and N2-(1-carboxyethyl)-7–1-hydroxy-2-oxopropyl-guanosine (MG-CEG). In cellular RNA and urine from patients, only the stereoisomers of CEG were detected. CEG levels were significantly elevated in patients with T2D compared to controls and showed a stronger association with T2D than the DNA adduct N2-(1-carboxyethyl)-deoxyguanosine (CEdG). Furthermore, CEG levels were higher in T2D patients who had developed complications compared to those without complications. Functionally, MG-modified luciferase mRNA exhibited decreased stability and reduced translational efficiency relative to unmodified mRNA. Conclusions: This study provides the first structural and functional characterization of MG-induced RNA adducts and demonstrates their accumulation in individuals with T2D, particularly in those with disease complications. These findings highlight RNA MG-adducts as clinically relevant epitranscriptomic modifications that may contribute to RNA destabilization and impaired translation, suggesting a novel molecular mechanism by which metabolic stress may exacerbate disease progression.http://www.sciencedirect.com/science/article/pii/S2212877825000936MethylglyoxalRNA damageDiabetesRNA stabilityRNA translation |
| spellingShingle | Edwin De Jesus Lopez Gonzalez SWT Lai Kelani Sun Caree R. Carson Carlos Hernandez-Castillo Tala Zoukari Kassandra Lopez Jianying Zhang Thomas Blevins John Termini Sarah C. Shuck Methylglyoxal-induced RNA modifications decrease RNA stability and translation and are associated with type 2 diabetes Molecular Metabolism Methylglyoxal RNA damage Diabetes RNA stability RNA translation |
| title | Methylglyoxal-induced RNA modifications decrease RNA stability and translation and are associated with type 2 diabetes |
| title_full | Methylglyoxal-induced RNA modifications decrease RNA stability and translation and are associated with type 2 diabetes |
| title_fullStr | Methylglyoxal-induced RNA modifications decrease RNA stability and translation and are associated with type 2 diabetes |
| title_full_unstemmed | Methylglyoxal-induced RNA modifications decrease RNA stability and translation and are associated with type 2 diabetes |
| title_short | Methylglyoxal-induced RNA modifications decrease RNA stability and translation and are associated with type 2 diabetes |
| title_sort | methylglyoxal induced rna modifications decrease rna stability and translation and are associated with type 2 diabetes |
| topic | Methylglyoxal RNA damage Diabetes RNA stability RNA translation |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000936 |
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