Investigating the importance of individual mitochondrial genotype in susceptibility to drug-induced toxicity

Abstract

The mitochondrion is an essential organelle responsible for generating cellular energy. Additionally, mitochondria are a source of inter-individual variation as they contain their own genome. Evidence has revealed that mitochondrial DNA (mtDNA) variation can confer differences in mitochondrial function and importantly, these differences may be a factor underlying the idiosyncrasies associated with unpredictable drug-induced toxicities. Thus far, preclinical and clinical data are limited but have revealed evidence in support of an association between mitochondrial haplogroup and susceptibility to specific adverse drug reactions. In particular, clinical studies have reported associations between mitochondrial haplogroup and antiretroviral therapy, chemotherapy and antibiotic-induced toxicity, although study limitations and conflicting findings mean that the importance of mtDNA variation to toxicity remains unclear. Several studies have used transmitochondrial cybrid cells as personalised models with which to study the impact of mitochondrial genetic variation. Cybrids allow the effects of mtDNA to be assessed against a stable nuclear background and thus the in vitro elucidation of the fundamental mechanistic basis of such differences. Overall, the current evidence supports the tenet that mitochondrial genetics represent an exciting area within the field of personalised medicine and drug toxicity. However, further research effort is required to confirm its importance. In particular, efforts should focus upon translational research to connect preclinical and clinical data that can inform whether mitochondrial genetics can be useful to identify at risk individuals or inform risk assessment during drug development.