Resilience associated with defects in Vitamin B12 metabolism: Balancing between homeostasis and disease.

CblC deficiency is an inborn error of intracellular Vitamin B12 (B12) metabolism caused by loss-of-function mutations in the MMACHC gene leading to metabolic decompensation, including homocysteine (Hcy) accumulation [1,2]. Cognitive impairment and variable disease onset among patients with identical mutations[1,3] motivates investigation of Hcy effects in a neural-like model and supports the concept of metabolic resilience, whereby cells maintain function despite biochemical defects [4]. SH-SY5Y neuroblastoma cells were cultured in B12-deprived media, differentiated into a neural-like phenotype, then exposed to increasing Hcy concentrations and recovered in unsupplemented or B12-supplemented conditions. This approach defined cytotoxic Hcy levels and explored changes in metabolomics, oxidative stress and protein and DNA methylation. Hcy induced dose-dependent cytotoxicity, with significant effects at higher doses, while B12 partially rescued viability. ¹H-NMR metabolomics identified key alterations. Exploratory analyses revealed compartment-specific methylation changes on a proteic level and treatment-specific DNA methylation changes. These findings support the concept of a metabolic tipping point, where Hcy-induced stress reveals limited resilience. Overall, this study highlights the interplay between metabolic imbalance, protein and epigenetic modulation in neural dysfunction.