Brunner, M.S., Habisch, H., Hafner, J., Mack, M., Novosiadla, Z., López Díaz, A.C., Wolinski, H., Rechberger, G.N., Eisenberg, T., Madl, T., Pertschy, B., Kühnlein, R.P., Tehlivets, O. (2026). Homocysteine and S-adenosyl-L-homocysteine impair development and methylation in yeast and flies.  Dis. Model Mech. 19(5): dmm052802.

FBrf0265531

Research paper

S-adenosyl-L-homocysteine (SAH), the product inhibitor of S-adenosyl-L-methionine-dependent methyltransferases, and its degradation product homocysteine (Hcy) are evolutionarily conserved master regulators of methylation metabolism, which is mediated by more than 200 methyltransferases in humans. Hyperhomocysteinemia (HHcy), characterized by elevated levels of Hcy in the blood, is an independent risk factor for atherosclerosis, a strong predictor of cardiovascular mortality and can cause associated pathology by interfering with methylation-dependent processes. Here, we developed a Drosophila melanogaster fly dietary model of HHcy and a Drosophila melanogaster genetic SAH accumulation model and compared them to corresponding Saccharomyces cerevisiae yeast models to reveal evolutionarily conserved methylation pattern changes responsive to elevation of Hcy levels. Feeding Drosophila an Hcy-containing diet or growing yeast on Hcy-supplemented medium, similarly to genetically blocking SAH degradation, led to SAH accumulation, developmental delay and growth defects. Furthermore, dietary or genetically induced SAH accumulation caused impaired phospholipid and protein methylation in both model organisms. Identification and functional characterization of evolutionarily conserved SAH-dependent methylation targets responsive to elevation of Hcy and/or SAH levels will reveal mechanisms of SAH toxicity in HHcy and help to decipher their role in associated pathologies.

PMC13312927 (PMC) (EuropePMC)