title: 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 NeuN+ 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.
  
  
  CONCLUSIONS
  For decades, it has been observed that vitamin B12 deficiency and multiple sclerosis (MS) share certain pathological changes, including conduction disturbances. In the present study, we have found that vitamin B12-dependent methionine metabolism is dysregulated in the MS brain. We found that concentrations of the methyl donor betaine are decreased in MS cortex and are correlated with reduced levels of the histone H3 methyl mark H3K4me3 in neurons. Cell culture and chromatin immunoprecipitation-seq data suggest that these changes may lead to defects in mitochondria and impact neuronal energetics. These data have uncovered a novel pathway linking methionine metabolism with mitochondrial respiration and have important implications for understanding mechanisms involved in neurodegeneration in MS.
authors.affiliation: Departments of Biological Sciences and.
authors.forename: Naveen Kumar
authors.initials: NK
authors.lastname: Singhal
authors.affiliation: Departments of Biological Sciences and Chemistry and Biochemistry, Kent State University, Kent, Ohio 44242.
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas 75226.
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.affiliation: Departments of Biological Sciences and.
authors.forename: Kholoud
authors.initials: K
authors.lastname: Alkhayer
authors.affiliation: Departments of Biological Sciences and.
authors.forename: Robert
authors.initials: R
authors.lastname: Clements
authors.affiliation: Departments of Biological Sciences and.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Sarcyk
authors.affiliation: Chemistry and Biochemistry, Kent State University, Kent, Ohio 44242.
authors.forename: Rohan S
authors.initials: RS
authors.lastname: Dassanayake
authors.affiliation: School of Applied Sciences, Auckland University of Technology, Auckland 1142, New Zealand, and.
authors.forename: Nicola E
authors.initials: NE
authors.lastname: Brasch
authors.affiliation: Departments of Biological Sciences and.
authors.forename: Ernest J
authors.initials: EJ
authors.lastname: Freeman
authors.affiliation: Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas 75226.
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.affiliation: Departments of Biological Sciences and jmcdonou@kent.edu.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McDonough
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D008715:Methionine / Q000378:metabolism*; D008745:Methylation; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology
chemical_list: D006657:Histones; D008715:Methionine
keywords: betaine; betaine homocysteine methyltransferase; epigenetics; methionine metabolism; mitochondria; multiple sclerosis