Valproic acid-induced hepatotoxicity in Alpers syndrome is associated with mitochondrial permeability transition pore opening-dependent apoptotic sensitivity in an induced pluripotent stem cell model.

Abstract

UNLABELLED:

Valproic acid (VPA) is widely used to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy, but potentially causes idiosyncratic liver injury. Alpers-Huttenlocher syndrome (AHS), a neurometabolic disorder caused by mutations in mitochondrial DNA polymerase gamma (POLG), is associated with an increased risk of developing fatal VPA hepatotoxicity. However, the mechanistic link of this clinical mystery remains unknown. Here, fibroblasts from 2 AHS patients were reprogrammed to induced pluripotent stem cells (iPSCs) and then differentiated to hepatocyte-like cells (AHS iPSCs-Hep). Both AHS iPSCs-Hep are more sensitive to VPA-induced mitochondrial-dependent apoptosis than controls, showing more activated caspase-9 and cytochrome c release. Strikingly, levels of both soluble and oligomeric optic atrophy 1, which together keep cristae junctions tight, are reduced in AHS iPSCs-Hep. Furthermore, POLG mutation cells show reduced POLG expression, mitochondrial DNA (mtDNA) amount, mitochondrial adenosine triphosphate production, as well as abnormal mitochondrial ultrastructure after differentiation to hepatocyte-like cells. Superoxide flashes, spontaneous bursts of superoxide generation, caused by opening of the mitochondrial permeability transition pore (mPTP), occur more frequently in AHS iPSCs-Hep. Moreover, the mPTP inhibitor, cyclosporine A, rescues VPA-induced apoptotic sensitivity in AHS iPSCs-Hep. This result suggests that targeting mPTP opening could be an effective method to prevent hepatotoxicity by VPA in AHS patients. In addition, carnitine or N-acetylcysteine, which has been used in the treatment of VPA-induced hepatotoxicity, is able to rescue VPA-induced apoptotic sensitivity in AHS iPSCs-Hep.

CONCLUSION:

AHS iPSCs-Hep are more sensitive to the VPA-induced mitochondrial-dependent apoptotic pathway, and this effect is mediated by mPTP opening. Toxicity models in genetic diseases using iPSCs enable the evaluation of drugs for therapeutic targets.

• Authors: Shengbiao Li, Jingyi Guo, Zhongfu Ying, Shen Chen, Liang Yang, Keshi Chen, Qi Long, Dajiang Qin, Duanqing Pei, Xingguo Liu
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 61 Issue 5 Pg. 1730-9 (May 2015) ISSN: 1527-3350 [Electronic] United States
• PMID: 25605636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Association for the Study of Liver Diseases.

Chemical References

• Anticonvulsants
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Valproic Acid

Topics

• Anticonvulsants (adverse effects)
• Apoptosis
• Cells, Cultured
• Chemical and Drug Induced Liver Injury (etiology)
• Diffuse Cerebral Sclerosis of Schilder (complications)
• Humans
• Induced Pluripotent Stem Cells
• Mitochondrial Membrane Transport Proteins (physiology)
• Mitochondrial Permeability Transition Pore
• Valproic Acid (adverse effects)