Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis.
Animals
Betaine
/ pharmacology
Betaine-Homocysteine S-Methyltransferase
/ metabolism
Cell Respiration
Cells, Cultured
Chromatin Assembly and Disassembly
Cuprizone
/ toxicity
Epigenesis, Genetic
Histone Code
Male
Mice
Mice, Inbred C57BL
Mitochondria
/ drug effects
Multiple Sclerosis
/ etiology
Neurons
/ drug effects
Rats
Rats, Sprague-Dawley
BHMT
H3K4me3
betaine
methionine metabolism
mitochondria
multiple sclerosis
Journal
Epigenetics
ISSN: 1559-2308
Titre abrégé: Epigenetics
Pays: United States
ID NLM: 101265293
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
pubmed:
26
2
2020
medline:
15
5
2021
entrez:
26
2
2020
Statut:
ppublish
Résumé
Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.
Identifiants
pubmed: 32096676
doi: 10.1080/15592294.2020.1735075
pmc: PMC7518703
doi:
Substances chimiques
Betaine
3SCV180C9W
Cuprizone
5N16U7E0AO
Betaine-Homocysteine S-Methyltransferase
EC 2.1.1.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
871-886Références
Neurochem Int. 2015 Nov;90:185-92
pubmed: 26340869
Eur J Clin Invest. 1996 Feb;26(2):167-70
pubmed: 8904527
BMC Cancer. 2013 Aug 17;13:389
pubmed: 23957506
J Neurosci. 2004 Oct 20;24(42):9434-40
pubmed: 15496679
Nutrients. 2017 Apr 29;9(5):
pubmed: 28468239
Neurochem Res. 2013 Nov;38(11):2385-96
pubmed: 24078261
Antioxid Redox Signal. 2014 Jun 1;20(16):2541-54
pubmed: 24124652
Biochim Biophys Acta. 2011 May;1812(5):630-41
pubmed: 21295140
J Clin Neurosci. 2009 Mar;16(3):399-403
pubmed: 19153046
Appl Physiol Nutr Metab. 2017 Nov;42(11):1228-1231
pubmed: 28715642
Biochem Biophys Res Commun. 2015 Jan 9;456(2):621-5
pubmed: 25498545
Epigenetics Chromatin. 2016 Sep 09;9(1):37
pubmed: 27617035
Nat Neurosci. 2014 Mar;17(3):357-66
pubmed: 24464041
FASEB J. 2009 Oct;23(10):3347-60
pubmed: 19497982
Arch Neurol. 1992 Jun;49(6):649-52
pubmed: 1596201
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Cell Metab. 2015 Nov 3;22(5):861-73
pubmed: 26411344
Am J Physiol Gastrointest Liver Physiol. 2010 Nov;299(5):G1068-77
pubmed: 20724529
Neuroscience. 2006 Nov 3;142(4):1245-53
pubmed: 16934409
Mol Med. 2012 May 09;18:628-35
pubmed: 22396019
Mol Cell. 2011 Mar 4;41(5):497-9
pubmed: 21362545
Biochem Soc Trans. 1994 Aug;22(3):296S
pubmed: 7821555
Dev Neurosci. 1998;20(4-5):271-6
pubmed: 9778562
Nat Chem Biol. 2015 Aug;11(8):571-578
pubmed: 26167872
Analyst. 2015 May 7;140(9):3057-63
pubmed: 25807213
Trends Mol Med. 2014 Mar;20(3):179-87
pubmed: 24369898
Neurochem Int. 2018 Jan;112:1-4
pubmed: 29080803
Electrophoresis. 2013 Jun;34(11):1710-6
pubmed: 23417555
Cell. 1999 Jul 9;98(1):115-24
pubmed: 10412986
Mol Biol Cell. 1999 Dec;10(12):4283-98
pubmed: 10588658
Cancer Cell. 2011 Nov 15;20(5):606-19
pubmed: 22094255
Biochim Biophys Acta. 2002 Jun 12;1590(1-3):93-102
pubmed: 12063172
J Neuroimmunol. 2013 Sep 15;262(1-2):128-31
pubmed: 23890807
Chemistry. 2011 Oct 10;17(42):11723-7
pubmed: 21922587
Biochemistry. 2017 Mar 14;56(10):1518-1528
pubmed: 28186720
Acta Neurol Scand Suppl. 2008;188:72-6
pubmed: 18439226
J Neurochem. 2013 Feb;124(3):388-96
pubmed: 23157378
J Neurosci. 2015 Nov 11;35(45):15170-86
pubmed: 26558787
J Neurol Sci. 2005 Jun 15;233(1-2):93-7
pubmed: 15896807
Parkinsonism Relat Disord. 2017 Nov;44:1-5
pubmed: 28807493
J Neural Transm (Vienna). 2004 Apr;111(4):547-67
pubmed: 15057524
Anal Biochem. 1995 Jul 1;228(2):323-9
pubmed: 8572314
J Nutr Biochem. 2011 Mar;22(3):242-51
pubmed: 20573497
Brain Res. 2008 Sep 10;1229:210-7
pubmed: 18657520
Int J Neurosci. 2018 Sep;128(9):835-841
pubmed: 29384421
Nucleic Acids Res. 2008 Jan;36(Database issue):D480-4
pubmed: 18077471
Neurobiol Aging. 2011 Feb;32(2):187-99
pubmed: 19329227
FASEB J. 2010 Aug;24(8):2804-17
pubmed: 20305127
Mol Cell. 2011 Mar 4;41(5):554-66
pubmed: 21362551
Neurology. 2005 Nov 8;65(9):1402-8
pubmed: 16275827
Can J Biochem. 1979 Jan;57(1):56-65
pubmed: 427630