title: Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts.
abstract: Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity. Here we studied the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. Our data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ UK.
authors.forename: Kamil S
authors.initials: KS
authors.lastname: Sitarz
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ UK; MRC Integrative Epidemiology Unit, Oakfield House, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Elliott
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ UK; Nijmegen Center for Mitochondrial Disorders, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Betül S
authors.initials: BS
authors.lastname: Karaman
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ UK; MRC Integrative Epidemiology Unit, Oakfield House, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Relton
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ UK. Electronic address: Rita.Horvath@ncl.ac.uk.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000187:drug effects; D019175:DNA Methylation; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000032:analysis; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D014635:Valproic Acid / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D004272:DNA, Mitochondrial; D014635:Valproic Acid; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human
keywords: Methylation; POLG; Toxicity; Valproic acid (VPA); mtDNA
references.citation: J Inherit Metab Dis. 2014 May;37(3):353-7
references.pmid: 24154984
references.citation: J Hepatol. 2011 Aug;55(2):426-34
references.pmid: 21147182
references.citation: Neurology. 1996 Feb;46(2):465-9
references.pmid: 8614514
references.citation: Anticancer Drugs. 2012 Nov;23(10):1054-66
references.pmid: 22863973
references.citation: Biochim Biophys Acta. 2007 Apr;1771(4):533-43
references.pmid: 17321204
references.citation: Hepatology. 2010 Nov;52(5):1791-6
references.pmid: 21038416
references.citation: Lancet. 2004 Sep 4-10;364(9437):875-82
references.pmid: 15351195
references.citation: Toxicol In Vitro. 2012 Jun;26(4):545-51
references.pmid: 22342442
references.citation: Chem Biol Interact. 1994 Mar;90(3):253-75
references.pmid: 8168173
references.citation: Ann Neurol. 2004 May;55(5):706-12
references.pmid: 15122711
references.citation: Neuromuscul Disord. 2008 Mar;18(3):259-67
references.pmid: 18160290
references.citation: Clin Toxicol (Phila). 2009 Feb;47(2):101-11
references.pmid: 19280426
references.citation: Mol Genet Metab. 2001 Aug;73(4):358-61
references.pmid: 11509020
references.citation: Hum Mol Genet. 2005 May 1;14(9):1171-82
references.pmid: 15772088
references.citation: Biochemistry. 1991 Jan 15;30(2):388-94
references.pmid: 1988037
references.citation: Hum Mol Genet. 2010 Aug 1;19(15):3043-52
references.pmid: 20484224
references.citation: Brain. 2006 Jul;129(Pt 7):1674-84
references.pmid: 16621917
references.citation: Lancet. 1987 Jan 3;1(8523):47-8
references.pmid: 2879132
references.citation: Cell Transplant. 2015;24(1):73-83
references.pmid: 24143888
references.citation: Clin Pharmacol Ther. 2011 Jun;89(6):867-74
references.pmid: 21544075
references.citation: Biochem Biophys Res Commun. 2009 Feb 6;379(2):578-82
references.pmid: 19118529
references.citation: Toxicol Sci. 2005 Aug;86(2):436-43
references.pmid: 15858222
references.citation: Epigenomics. 2012 Jun;4(3):325-41
references.pmid: 22690668