Effect of Valproic Acid on Mitochondrial Epigenetics

Overview

Journal Eur J Pharmacol

Specialty Pharmacology

Date 2012 Jun 26

PMID 22728245

Citations 35

Authors

Hu Chen

Svetlana Dzitoyeva

Hari Manev

Affiliations

Soon will be listed here.

Abstract

Valproic acid (valproate), an anticonvulsant and a mood stabilizer, is a potent histone deacetylase inhibitor and a widely utilized pharmacological tool for neuroepigenetic research including DNA methylation. However, only nuclear but not mitochondrial DNA (mtDNA) has been investigated for the effects of valproate on the formation of 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5 hmC). Using mouse 3T3-L1 cells, we investigated the effects of short (1 day) and prolonged (3 days) valproate treatment on global mtDNA 5 mC content, global and mtDNA sequence-specific 5 hmC content, mRNA levels for ten-eleven-translocation (TET) enzymes involved in 5 hmC formation, and the mitochondrial content of TET proteins. Only 5 hmC but not 5 mC content in mtDNA was affected (decreased) by valproate, and only after the prolonged treatment. This action of valproate was mimicked by MS-275, a class I histone deacetylase inhibitor. The prolonged but not the short valproate treatment decreased the expression of Tet1 mRNA and reduced the mitochondrial content of the TET1 protein. Hence, a likely scenario for a valproate-induced 5 hmC decrease in mtDNA may involve nuclear histone deacetylase inhibition (mitochondria do not contain histones) causing the initial increase of Tet1 transcription, which is followed by a delayed compensatory decrease of Tet1 expression and a reduced presence of TET1 protein in mitochondria. Further research is needed to elucidate the functional implications of epigenetic modifications of mtDNA. The observed effects of valproate on mitochondrial epigenetics may have implications for a better understanding of both therapeutic and unwanted effects of this drug and possibly other histone deacetylase inhibitors.

Citing Articles

Mitochondrial Dysfunction as a Biomarker of Illness State in Bipolar Disorder: A Critical Review.

Gimenez-Palomo A, Andreu H, De Juan O, Olivier L, Ochandiano I, Ilzarbe L Brain Sci. 2025; 14(12.

PMID: 39766398 PMC: 11674880. DOI: 10.3390/brainsci14121199.

Therapeutic potential of tLyp-1-EV-shCTCF in inhibiting liver cancer stem cell self-renewal and immune escape via SALL3 modulation in hepatocellular carcinoma.

Zhu H, Xie Z Transl Oncol. 2024; 49:102048.

PMID: 39186862 PMC: 11388803. DOI: 10.1016/j.tranon.2024.102048.

Mitochondrial epigenetic modifications and nuclear-mitochondrial communication: A new dimension towards understanding and attenuating the pathogenesis in women with PCOS.

Shukla P, Melkani G Rev Endocr Metab Disord. 2023; 24(2):317-326.

PMID: 36705802 PMC: 10150397. DOI: 10.1007/s11154-023-09789-2.

Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-]pyrrole Chelators.

Antonyova V, Tatar A, Brogyanyi T, Kejik Z, Kaplanek R, Vellieux F Int J Mol Sci. 2022; 23(18).

PMID: 36142763 PMC: 9505425. DOI: 10.3390/ijms231810850.

Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective.

Pina-Sanchez P, Chavez-Gonzalez A, Ruiz-Tachiquin M, Vadillo E, Monroy-Garcia A, Montesinos J Cancer Control. 2021; 28:10732748211038735.

PMID: 34565215 PMC: 8481752. DOI: 10.1177/10732748211038735.

References

Sakharkar A, Zhang H, Tang L, Shi G, Pandey S . Histone deacetylases (HDAC)-induced histone modifications in the amygdala: a role in rapid tolerance to the anxiolytic effects of ethanol. Alcohol Clin Exp Res. 2011; 36(1):61-71. PMC: 3208078. DOI: 10.1111/j.1530-0277.2011.01581.x. View

Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J . Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell. 2011; 42(4):451-64. PMC: 3099128. DOI: 10.1016/j.molcel.2011.04.005. View

Iyer L, Tahiliani M, Rao A, Aravind L . Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle. 2009; 8(11):1698-710. PMC: 2995806. DOI: 10.4161/cc.8.11.8580. View

Finsterer J, Mahjoub S . Mitochondrial toxicity of antiepileptic drugs and their tolerability in mitochondrial disorders. Expert Opin Drug Metab Toxicol. 2011; 8(1):71-9. DOI: 10.1517/17425255.2012.644535. View

Jergil M, Forsberg M, Salter H, Stockling K, Gustafson A, Dencker L . Short-time gene expression response to valproic acid and valproic acid analogs in mouse embryonic stem cells. Toxicol Sci. 2011; 121(2):328-42. DOI: 10.1093/toxsci/kfr070. View

Tsai L, Leng Y, Wang Z, Leeds P, Chuang D . The mood stabilizers valproic acid and lithium enhance mesenchymal stem cell migration via distinct mechanisms. Neuropsychopharmacology. 2010; 35(11):2225-37. PMC: 3055307. DOI: 10.1038/npp.2010.97. View

Tahiliani M, Koh K, Shen Y, Pastor W, Bandukwala H, Brudno Y . Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009; 324(5929):930-5. PMC: 2715015. DOI: 10.1126/science.1170116. View

Phiel C, Zhang F, Huang E, Guenther M, Lazar M, Klein P . Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001; 276(39):36734-41. DOI: 10.1074/jbc.M101287200. View

Weaver I, Cervoni N, Champagne F, DAlessio A, Sharma S, Seckl J . Epigenetic programming by maternal behavior. Nat Neurosci. 2004; 7(8):847-54. DOI: 10.1038/nn1276. View

10.

Flax J, Soloway P . Methylation on the mind. Nat Neurosci. 2011; 14(12):1494-6. DOI: 10.1038/nn.2988. View

11.

Chestnut B, Chang Q, Price A, Lesuisse C, Wong M, Martin L . Epigenetic regulation of motor neuron cell death through DNA methylation. J Neurosci. 2011; 31(46):16619-36. PMC: 3238138. DOI: 10.1523/JNEUROSCI.1639-11.2011. View

12.

Levenson J, Roth T, Lubin F, Miller C, Huang I, Desai P . Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem. 2006; 281(23):15763-73. DOI: 10.1074/jbc.M511767200. View

13.

Smalheiser N, Lugli G, Thimmapuram J, Cook E, Larson J . Mitochondrial small RNAs that are up-regulated in hippocampus during olfactory discrimination training in mice. Mitochondrion. 2011; 11(6):994-5. PMC: 3717332. DOI: 10.1016/j.mito.2011.08.014. View

14.

Irier H, Jin P . Dynamics of DNA methylation in aging and Alzheimer's disease. DNA Cell Biol. 2012; 31 Suppl 1:S42-8. PMC: 3461976. DOI: 10.1089/dna.2011.1565. View

15.

Grayson D, Kundakovic M, Sharma R . Is there a future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders?. Mol Pharmacol. 2009; 77(2):126-35. DOI: 10.1124/mol.109.061333. View

16.

Siegmund K, Connor C, Campan M, Long T, Weisenberger D, Biniszkiewicz D . DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS One. 2007; 2(9):e895. PMC: 1964879. DOI: 10.1371/journal.pone.0000895. View

17.

Kundakovic M, Chen Y, Guidotti A, Grayson D . The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. Mol Pharmacol. 2008; 75(2):342-54. PMC: 2684898. DOI: 10.1124/mol.108.051763. View

18.

Imbesi M, Dzitoyeva S, Ng L, Manev H . 5-Lipoxygenase and epigenetic DNA methylation in aging cultures of cerebellar granule cells. Neuroscience. 2009; 164(4):1531-7. PMC: 2783316. DOI: 10.1016/j.neuroscience.2009.09.039. View

19.

Dong E, Chen Y, Gavin D, Grayson D, Guidotti A . Valproate induces DNA demethylation in nuclear extracts from adult mouse brain. Epigenetics. 2010; 5(8):730-5. DOI: 10.4161/epi.5.8.13053. View

20.

Kazantsev A, Thompson L . Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov. 2008; 7(10):854-68. DOI: 10.1038/nrd2681. View