Mechanism of valproic acid-induced hepatotoxicity in alpers syndrome using an induced pluripotent stem cell model

Valproic acid (VPA) is a widely used antiepileptic drug to treat epilepsy and psychiatric disorders, but potentially causes idiosyncratic liver injury. Alpers-Huttenlocher syndrome (AHS), a neurogenetic disorder caused by mitochondrial DNA polymerase γ (POLG) mutations, has close correlation with fatal VPA hepatotoxicity. However, the mechanisms of this clinical mystery remain unknown. Here, we established an induced pluripotent stem cell (iPSC) toxicity model to explore the mechanism behind the high risk of VPA-induced liver injury in AHS. By this model, we demonstrated that AHS iPSCs-hepatocytes are more sensitive to VPA-induced mitochondrial-dependent apoptosis than controls. Furthermore, superoxide flashes, new spontaneous bursts of superoxide generation triggered by transient openings of the mitochondrial permeability transition pore (mPTP), occur more frequently in AHS iPSCs-hepatocytes. The mPTP inhibitor, cyclosporine A, is able to rescue VPA-induced apoptotic sensitivity. In addition, carnitine and N-acetylcysteine (NAC), which has been used to treat VPA-induced liver injury, also rescue VPA-induced apoptotic sensitivity.