Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts

Autor: Kamil S, Sitarz, Hannah R, Elliott, Betül S, Karaman, Caroline, Relton, Patrick F, Chinnery, Rita, Horvath
Rok vydání: 2014
Předmět:
Adult
Male
CPEO
chronic progressive external ophthalmoplegia (OMIM: 157640)
NEAA
non-essential amino acids
DNA Copy Number Variations
AHS
Alpers–Huttenlocher syndrome (OMIM: 203700)
Valproic acid (VPA)
DNA-Directed DNA Polymerase
POLG
polymerase γ
DNA
Mitochondrial
Methylation
Article
PVDF
polyvinylidene difluoride
cDNA
complementary DNA
MEM
minimal essential medium
FBS
fetal bovine serum
VPA
valproic acid/sodium valproate
Humans
Cells
Cultured
Toxicity
mtDNA
Valproic Acid
SANDO
sensory ataxia
neuropathy
dysarthria
ophthalmoplegia (OMIM: 607459)
Infant
HRP
horseradish peroxidase
DNA Methylation
Fibroblasts
Middle Aged
DNA Polymerase gamma
Mitochondria
mtDNA
mitochondrial DNA
Gene Expression Regulation
POLG
Child
Preschool
lipids (amino acids
peptides
and proteins)
Female
BSA
bovine serum albumin
MIRAS
mitochondrial recessive ataxia syndrome
Zdroj: Molecular Genetics and Metabolism
ISSN: 1096-7206
Popis: 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.
Highlights • VPA caused the increased expression of POLG and other mitochondrial proteins in vitro. • Elevated mtDNA copy number confirmed the effect of VPA on mitochondrial biogenesis. • POLG-deficient cells cannot address the increased metabolic rate triggered by VPA. • Altered DNA methylation is unlikely to contribute to POLG-mediated VPA toxicity.
Databáze: OpenAIRE
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