PUBLICATION
Combined loss of glyoxalase 1 and aldehyde dehydrogenase 3a1 amplifies dicarbonyl stress, impairs proteasome activity resulting in hyperglycemia and activated retinal angiogenesis
- Authors
- Li, S., Li, H., Bennewitz, K., Poschet, G., Buettner, M., Hausser, I., Szendroedi, J., Nawroth, P.P., Kroll, J.
- ID
- ZDB-PUB-250202-13
- Date
- 2025
- Source
- Metabolism: clinical and experimental : 156149156149 (Journal)
- Registered Authors
- Kroll, Jens
- Keywords
- ALDH3A1, Diabetes, Diabetic retinopathy, Dicarbonyl stress, GLO1, MG-derived hydroimidazolone 1 (MG-H1), Proteasome dysfunction, Zebrafish
- MeSH Terms
-
- Retinal Neovascularization/genetics
- Retinal Neovascularization/metabolism
- Retinal Neovascularization/pathology
- Glycation End Products, Advanced/metabolism
- Animals, Genetically Modified
- Gene Knockout Techniques
- Proteasome Endopeptidase Complex*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Pyruvaldehyde/metabolism
- Aldehyde Dehydrogenase/genetics
- Aldehyde Dehydrogenase/metabolism
- Lactoylglutathione Lyase*/genetics
- Lactoylglutathione Lyase*/metabolism
- Angiogenesis
- Zebrafish*
- Animals
- Hyperglycemia*/metabolism
- PubMed
- 39892865 Full text @ Metab. Clin. Exp.
Citation
Li, S., Li, H., Bennewitz, K., Poschet, G., Buettner, M., Hausser, I., Szendroedi, J., Nawroth, P.P., Kroll, J. (2025) Combined loss of glyoxalase 1 and aldehyde dehydrogenase 3a1 amplifies dicarbonyl stress, impairs proteasome activity resulting in hyperglycemia and activated retinal angiogenesis. Metabolism: clinical and experimental. :156149156149.
Abstract
Background & aims Any energy consumption results in the generation of highly reactive dicarbonyls and the need to prevent excessive dicarbonyls accumulation through the activity of several interdependent detoxification enzymes. Glyoxalase 1 (GLO1) knockout zebrafish showed only moderately elevated methylglyoxal (MG) levels, but increased Aldehyde Dehydrogenases (ALDH) activity and increased aldh3a1 expression. Elevated levels of 4-hydroxynonenal (4-HNE) but no MG increase were observed in ALDH3A1KO. The question of whether ALDH3A1 prevents MG formation as a compensatory mechanism in the absence of GLO1 remained unclear.
Methods To investigate whether ALDH3A1 detoxifies MG as a compensatory mechanism in the absence of GLO1, the GLO1/ALDH3A1 double knockout (DKO) zebrafish was first generated. Various metabolites including advanced glycation end products (AGEs), as well as glucose metabolism and hyaloid vasculature were analyzed in GLO1KO, ALDH3A1KO and GLO1/ALDH3A1DKO zebrafish.
Results In the absence of GLO1 and ALDH3A1, MG-H1 levels were increased. MG-H1 accumulation led to a severe deterioration of proteasome function, resulting in impaired glucose homeostasis and consequently amplified angiogenic activation of the hyaloid and retinal vasculature. Rescue of these pathological processes could be observed by using L-carnosine, and proteasome activator betulinic acid.
Conclusion The present data, together with previous studies, suggest that ALDH3A1 and GLO1 are important detoxification enzymes that prevent the deleterious effects of MG-H1 accumulation on proteasome function, glucose homeostasis and vascular function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping