Personalised mitochondrial health: a functional and multi-omic assessment to predict individual susceptibility to hepatoxicity of antiepileptic drugs

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The realisation that mitochondrial genetics are an important, and under-researched, factor in personalised medicine is growing. This recognition prompted the establishment of a unique, integrative program at the MRC Centre for Drug Safety Science (CDSS) in 2014 in order to define the role of mitochondrial genetics in the onset of adverse drug reactions and this studentship seeks to continue and strengthen this successful research program. As such aim of this studentship is to evaluate the role of individual mitochondrial function and genetics in determining the risk of patients developing hepatotoxicity to a panel of anti-epileptic drugs (AED) associated with drug-induced liver injury (DILI). An integrated, multi-omic approach will be utilised in which functional, genomic, proteomic and metabolomic investigations are performed in tandem supported by specialised bioinformatic analysis. Many anti-epileptic drugs (AED) are associated with adverse effects on the liver and are known to induce mitochondrial dysfunction. These encompass a range of severity from rare idiosyncratic life-threatening , such as hepatotoxicity associated with sodium valproate which can cause acute liver failure in a small-number of patients, to transient, elevations in liver ALT levels, encountered by many patients taking drugs such as carbamazepine. Understanding more clearly the genetic and mechanistic factors predisposing to these adverse effects and their severity will inform the safer, targeted use of these drugs. This approach requires the use of an advanced in vitro model; a panel of liver-specific transmitochondrial cybrids. Essentially in this method we can replace the mitochondrial DNA (mtDNA) of a standard laboratory model cell (HepG2) with mtDNA from volunteers or patients using their platelets as the mtDNA donor, thus allowing the reproducible examination of the effects of individual mtDNA against a constant nuclear background. The cybrids will be utilised to elucidate the molecular and chemical pathways linking mitochondrial dysfunction and cell death and furthermore to investigate the effect of mitochondrial genetic and epigenetic variation on sensitivity to AEDs. Finally, quantitative metabolomic and proteomic investigations will seek to identify potential biomarkers of susceptibility or toxicity.