Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression.
Acetate-CoA Ligase
/ metabolism
Acetyl Coenzyme A
/ metabolism
Acetylation
DNA Polymerase gamma
/ metabolism
DNA, Mitochondrial
/ genetics
Dinoprostone
/ metabolism
Epigenesis, Genetic
/ genetics
Gene Expression
/ drug effects
Genetic Loci
/ genetics
HEK293 Cells
Histone Acetyltransferases
/ metabolism
Histones
/ metabolism
Humans
Ketoglutaric Acids
/ pharmacology
Mitochondria
/ enzymology
Promoter Regions, Genetic
/ genetics
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
29
10
2018
revised:
28
01
2019
accepted:
29
01
2019
entrez:
10
2
2019
pubmed:
10
2
2019
medline:
10
2
2019
Statut:
epublish
Résumé
The impact of mitochondrial dysfunction in epigenetics is emerging, but our understanding of this relationship and its effect on gene expression remains incomplete. We previously showed that acute mitochondrial DNA (mtDNA) loss leads to histone hypoacetylation. It remains to be defined if these changes are maintained when mitochondrial dysfunction is chronic and if they alter gene expression. To fill these gaps of knowledge, we here studied a progressive and a chronic model of mtDNA depletion using biochemical, pharmacological, genomics, and genetic assays. We show that histones are primarily hypoacetylated in both models. We link these effects to decreased histone acetyltransferase activity unrelated to changes in ATP citrate lyase, acetyl coenzyme A synthetase 2, or pyruvate dehydrogenase activities, which can be reversibly modulated by altering the mitochondrial pool of acetyl-coenzyme A. Also, we determined that the accompanying changes in histone acetylation regulate locus-specific gene expression and physiological outcomes, including the production of prostaglandins. These results may be relevant to the pathophysiology of mtDNA depletion syndromes and to understanding the effects of environmental agents that lead to physical or functional mtDNA loss.
Identifiants
pubmed: 30737248
pii: 2/1/e201800228
doi: 10.26508/lsa.201800228
pmc: PMC6369536
pii:
doi:
Substances chimiques
DNA, Mitochondrial
0
Histones
0
Ketoglutaric Acids
0
Acetyl Coenzyme A
72-89-9
Histone Acetyltransferases
EC 2.3.1.48
DNA Polymerase gamma
EC 2.7.7.7
POLG protein, human
EC 2.7.7.7
Acetate-CoA Ligase
EC 6.2.1.1
Dinoprostone
K7Q1JQR04M
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2019 Lozoya et al.
Références
Free Radic Biol Med. 2012 Dec 1;53(11):2178-87
pubmed: 23022407
Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):E4033-42
pubmed: 25192935
Brief Bioinform. 2017 Mar 1;18(2):279-290
pubmed: 26979602
Cell. 2014 Jul 3;158(1):84-97
pubmed: 24995980
J Cell Sci. 2005 Dec 15;118(Pt 24):5825-34
pubmed: 16317046
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
Nat Cell Biol. 2017 Jun;19(6):626-638
pubmed: 28504707
Cell Rep. 2016 Oct 18;17(4):1037-1052
pubmed: 27760311
Cold Spring Harb Protoc. 2009 Sep;2009(9):pdb.prot5278
pubmed: 20147263
PLoS Biol. 2018 Apr 18;16(4):e2005707
pubmed: 29668680
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6
pubmed: 21106759
Nature. 2017 Jun 15;546(7658):381-386
pubmed: 28562591
BMC Bioinformatics. 2013 Apr 15;14:128
pubmed: 23586463
Biochemistry. 2013 Aug 27;52(34):5746-59
pubmed: 23862699
EMBO J. 2014 Oct 1;33(19):2142-56
pubmed: 25107473
Database (Oxford). 2016 May 02;2016:
pubmed: 27141089
Nucleic Acids Res. 2016 Jan 4;44(D1):D7-19
pubmed: 26615191
PLoS One. 2013;8(2):e54896
pubmed: 23437046
Mol Cell. 2014 Mar 6;53(5):710-25
pubmed: 24560926
Mol Cell. 2010 Jul 9;39(1):121-32
pubmed: 20603080
J Biol Chem. 2003 Jan 17;278(3):1728-34
pubmed: 12424245
Mol Cell. 2016 Jan 21;61(2):199-209
pubmed: 26725009
Am J Pathol. 2012 Jan;180(1):24-31
pubmed: 22056359
Appl Opt. 2009 Apr 1;48(10):D20-5
pubmed: 19340110
Cell. 2011 Jan 7;144(1):79-91
pubmed: 21215371
Cell Metab. 2018 May 01;27(5):1007-1025.e5
pubmed: 29657030
J Cell Biol. 2018 Jul 2;217(7):2247-2259
pubmed: 29760106
Am J Physiol Endocrinol Metab. 2008 Jun;294(6):E995-1010
pubmed: 18349109
Cancer Metab. 2015 Sep 23;3:10
pubmed: 26401273
Epigenetics. 2012 Apr;7(4):326-34
pubmed: 22419065
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Genome Res. 2002 Jun;12(6):996-1006
pubmed: 12045153
Science. 2009 May 22;324(5930):1076-80
pubmed: 19461003
Cell Rep. 2017 Jan 17;18(3):647-658
pubmed: 28099844
Science. 1989 Oct 27;246(4929):500-3
pubmed: 2814477
BMC Bioinformatics. 2016 Oct 3;17(1):404
pubmed: 27716038
Mol Cell. 2006 Aug;23(4):607-18
pubmed: 16916647
Methods. 2004 May;33(1):81-5
pubmed: 15039090
Cold Spring Harb Symp Quant Biol. 2009;74:383-93
pubmed: 19955254
Toxicol Sci. 2013 Jul;134(1):1-17
pubmed: 23629515
Genes Dev. 2018 Apr 1;32(7-8):497-511
pubmed: 29674394
Curr Protoc Bioinformatics. 2014 Sep 08;47:11.12.1-34
pubmed: 25199790
ACS Chem Biol. 2015 Jan 16;10(1):95-108
pubmed: 25562692
Biochemistry. 2000 Feb 8;39(5):1169-79
pubmed: 10653665
Cell. 2013 Dec 19;155(7):1624-38
pubmed: 24360282
Biochim Biophys Acta. 2016 Oct;1864(10):1372-401
pubmed: 27296530
EMBO Rep. 2003 Oct;4(10):944-7
pubmed: 14528264
Nat Rev Genet. 2011 Jan;12(1):7-18
pubmed: 21116306
EMBO Rep. 2015 Nov;16(11):1467-81
pubmed: 26474904
Nat Protoc. 2007;2(6):1445-57
pubmed: 17545981
Cancer Biol Ther. 2008 Aug;7(8):1182-90
pubmed: 18458531