Methyl Donors, Epigenetic Alterations, and Brain Health: Understanding the Connection

Abstract

Methyl donors such as choline, betaine, folic acid, methionine, and vitamins B6 and B12 are critical players in the one-carbon metabolism and have neuroprotective functions. The one-carbon metabolism comprises a series of interconnected chemical pathways that are important for normal cellular functions. Among these pathways are those of the methionine and folate cycles, which contribute to the formation of S-adenosylmethionine (SAM). SAM is the universal methyl donor of methylation reactions such as histone and DNA methylation, two epigenetic mechanisms that regulate gene expression and play roles in human health and disease. Epigenetic mechanisms have been considered a bridge between the effects of environmental factors, such as nutrition, and phenotype. Studies in human and animal models have indicated the importance of the optimal levels of methyl donors on brain health and behavior across the lifespan. Imbalances in the levels of these micronutrients during critical periods of brain development have been linked to epigenetic alterations in the expression of genes that regulate normal brain function. We present studies that support the link between imbalances in the levels of methyl donors, epigenetic alterations, and stress-related disorders. Appropriate levels of these micronutrients should then be monitored at all stages of development for a healthier brain.

TRPV4‐mediated Ca2+ deregulation causes mitochondrial dysfunction via the AKT/α‐synuclein pathway in dopaminergic neurons

“…FA produces S‐adenosylmethionine, the universal methyl donor for methylation reactions, via one‐carbon metabolism and contributes to the epigenetic regulation of gene expression, including CpG methylation 31 . CpG methylation status in the regulatory regions of SNCA is involved in the transcriptional regulation of α‐syn expression 40 .…”

“…This is possibly a mechanism involved in the developmental defects of MD‐DNs 26 . In the current study, FA was tested as a potential therapeutic candidate targeting mitochondrial factors to ameliorate the developmental defects of MD‐DNs 28–31 . FA normalized mitochondrial Ca 2+ , ROS levels, and MMPs, and restored ATP levels, improving neurite outgrowth in MD‐DNs.…”

“…Contrastingly, folic acid (FA) is a well‐established and widely recommended natural supplement for pregnant women 27 that prevents birth defects, including neural tube defects. Although the exact mechanisms of its action are not fully understood yet, FA exerts its effects via multiple mechanisms, including epigenetic regulation as a methyl donor in one‐carbon metabolism, mitochondrial activation, and direct reactive oxygen species (ROS) scavenging 28–31 . In the present study, the neurodevelopmental defects in MD‐DNs were further tested using FA, and the neuropathological association between TRPV4‐mediated Ca 2+ deregulation and Ca 2+ overload‐induced mitochondrial pathology was examined based on the pharmacological effects of FA.…”

The effects of essential oil from Lippia origanoides and herbal betaine on performance, intestinal integrity, bone mineralization and meat quality in broiler chickens subjected to cyclic heat stress

“…Enzymes, proteins, and membranes are unaffected by this buildup. Betaine is a growing biological methyl donor ( Bekdash, 2023 ). Betaine increases energy metabolism enzyme activity and reduces liver fat in hens ( Sun L et al, 2023 ).…”

Integrated analysis of the association between methionine cycle and risk of moyamoya disease

“…In recent years, metabolomics has become an increasingly powerful tool in the identification and validation of biomarkers for various diseases. Methionine (Met) cycle was a complex metabolic pathway with important regulatory functions in cellular processes such as DNA synthesis, methylation, and redox balance 11–13 . The altered levels of Met cycle‐related metabolites played a crucial role in the pathogenesis and progression of cardiovascular and cerebrovascular diseases 14,15 .…”