Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis

Abstract

Mitochondrial changes, including decreased expression of electron transport chain subunit genes and impaired energetic, have been reported in multiple sclerosis (MS), but the mechanisms involved in these changes are not clear. To determine whether epigenetic mechanisms are involved, we measured the concentrations of methionine metabolites by liquid chromatography tandem mass spectrometry, histone H3 methylation patterns, and markers of mitochondrial respiration in gray matter from postmortem MS and control cortical samples. We found decreases in respiratory markers as well as decreased concentrations of the methionine metabolites S-adenosylmethionine, betaine, and cystathionine in MS gray matter. We also found expression of the enzyme betaine homocysteine methyltransferase in cortical neurons. This enzyme catalyzes the remethylation of homocysteine to methionine, with betaine as the methyl donor, and has previously been thought to be restricted to liver and kidney in the adult human. Decreases in the concentration of the methyl donor betaine were correlated with decreases in histone H3 trimethylation (H3K4me3) in NeuNϩ neuronal nuclei in MS cortex compared with controls. Mechanistic studies demonstrated that H3K4me3 levels and mitochondrial respiration were reduced in SH-SY5Y cells after exposure to the nitric oxide donor sodium nitroprusside, and betaine was able to rescue H3K4me3 levels and respiratory capacity in these cells. Chromatin immunoprecipitation experiments showed that betaine regulates metabolic genes in human SH-SY5Y neuroblastoma cells. These data suggest that changes to methionine metabolism may be mechanistically linked to changes in neuronal energetics in MS cortex.

Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology

“…Neurons with longer projections require increased ATP to maintain ion homeostasis and conduction of nerve impulses over long distances. Our data show that Hbb overexpression in SH-SY5Y neuroblastoma cells increased H3K4me3, a histone mark that is present in actively transcribed regions of chromatin and regulates expression of oxidative phosphorylation genes (Singhal et al 2015). A role for hemoglobin in mitochondrial respiration is supported by a study by Biagoli et al (2009) which suggested that alterations in hemoglobin expression affect cellular energetics, since dopaminergic cell lines over expressing α- and β-globin subunits exhibited changes in oxygen homeostasis and alterations in the expression of mitochondrial genes.…”

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…Chromatin immunoprecipitation findings showed that betaine regulates metabolic genes in SH-SY5Y neuroblastoma cells. These data suggest that altered methionine metabolism may be tied to changes in neuronal energetics in multiple sclerosis cortex (Singhal et al, 2015).…”

“…This is evident by overt epigenetic modifications in cardiovascular anomalies including coronary heart disease, hypertension, peripheral vascular disease and stroke in the presence of major pro-epigenetic cardiovascular risk factors such as aging, high fat/caloric intake, exercise, drinking and tobacco abuse (Whayne, 2015). In addition, prevalence of cardiovascular diseases in adulthood is tightly controlled by early developmental factors such as gene imprinting, amniotic sac development, maternal and fetal nutritional status, among others (Horvath et al, 2014;Singhal et al, 2015;Thornburg, 2015). Through these epigenetic modifications, there may be infinite developmental cardiovascular benefit/harm for the fetus and newborn later on in adult life health status.…”

Nicotinamide metabolism regulates glioblastoma stem cell maintenance

“…Here, we show that mesenchymal GSCs preferentially activate 2 distinctive features ─ DNA hypomethylation and NAD + utilization ─ due to a switch in NAM metabolism regulated by high levels of NNMT and NAMPT (Supplemental Figure 2B). To date, functional contributions of NNMT to diet-induced obesity, insulin resistance, glucose, lipid, and cholesterol metabolism have been delineated (63,64). However, the oncogenic mechanisms of NNMT are poorly understood, despite high expression levels in many cancers, including GBM.…”

“…Although N-methylation of histones is closely associated with functional changes of chromatin and, thus, is involved in cell biology (63,66), N-methylation of metabolites may serve as a point of fragility for tumor cells due to simultaneous effects on both metabolism and epigenetic modifications, as demonstrated by efficacy of NAMPT inhibitors in IDH1 mutant or MYC-amplified gliomas (67, 68). Further, NAMPT may regulate GBM sphere-forming cells through regulation of the inhibitor of differentiation (ID) pathway (69).…”