Mitochondrial Hepatopathies: Advances in Genetics, Therapeutic Approaches, and Outcomes

Lee, Way Seah; Sokol, Ronald J.

doi:10.1016/j.jpeds.2013.05.036

Cited by 58 publications

(52 citation statements)

References 56 publications

(99 reference statements)

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“…Mitochondrial hepatopathies are disorders in which dysfunction of hepatocyte mitochondria plays a key role in the pathogenesis of liver injury or failure . Mitochondrial hepatopathies are divided into primary and secondary disorders according to genetic or contextual reasons .…”

mentioning

confidence: 99%

“…Mitochondrial hepatopathies are the most important causes of acute liver failure (ALF). Although various therapies and novel molecules have been advocated, no effective therapy for mitochondrial hepatopathies is available, particularly for genetic disorders (e.g., mitochondrial DNA [mtDNA] depletion syndrome and Alpers syndrome) with compound clinical features …”

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confidence: 99%

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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

Guo

Ying

et al. 2015

Hepatology

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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 VPAinduced 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. (HEPATOLOGY 2015;61:1730-1739

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confidence: 99%

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confidence: 99%

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

Guo

Ying

et al. 2015

Hepatology

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“…The mechanism is largely unknown, but a recent study demonstrated that inhibition of mitochondrial permeability transition pore opening could rescue valproate induced apoptosis in hepatocytes with POLG mutations [14]. Mitochondrial hepatopathies are another important cause of ALF in children, reflecting this age group's increased susceptibility [2,15,16].…”

Section: Host Factorsmentioning

confidence: 99%

Drug-induced liver injury in children

Amin

Harpavat

Leung

2015

Current Opinion in Pediatrics

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“…Liver biopsy usually shows microvesicular steatosis and mtDNA depletion in VPA‐ALF, but pretransplant liver biopsy is rarely feasible. In contrast to many other mitochondrial energy disorders, muscle mtDNA depletion or impaired mitochondrial respiratory chain function is rarely found in VPA‐ALF …”

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confidence: 90%

“…A number of similar reports followed, and in 2011, Mindikoglu et al described a series of 17 children with VPA‐ALF undergoing transplantation: 14 died within 1 year, and there were no long‐term survivors. Not surprisingly, VPA‐ALF has been considered an absolute contraindication to LT …”

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confidence: 99%

Acute liver failure after valproate exposure: Liver transplantation may be indicated beyond childhood

McKiernan

2014

Liver Transpl

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Mitochondrial Hepatopathies: Advances in Genetics, Therapeutic Approaches, and Outcomes

Cited by 58 publications

References 56 publications

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

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

Drug-induced liver injury in children

Acute liver failure after valproate exposure: Liver transplantation may be indicated beyond childhood

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