Abstract
Mitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions. Despite these findings, there are currently limited models to assess the effect of mtDNA variation upon susceptibility to adverse drug reactions. Platelets offer a potential personalised model of this variation, as their anucleate nature offers a source of mtDNA without interference from the nuclear genome. This study, therefore, aimed to determine the effect of mtDNA variation upon mitochondrial function and drug-induced mitochondrial dysfunction in a platelet model. The mtDNA haplogroup of 383 healthy volunteers was determined using next-generation mtDNA sequencing (Illumina MiSeq). Subsequently, 30 of these volunteers from mitochondrial haplogroups H, J, T and U were recalled to donate fresh, whole blood from which platelets were isolated. Platelet mitochondrial function was tested at basal state and upon treatment with compounds associated with both mitochondrial dysfunction and adverse drug reactions, flutamide, 2-hydroxyflutamide and tolcapone (10–250 μM) using extracellular flux analysis. This study has demonstrated that freshly-isolated platelets are a practical, primary cell model, which is amenable to the study of drug-induced mitochondrial dysfunction. Specifically, platelets from donors of haplogroup J have been found to have increased susceptibility to the inhibition of complex I-driven respiration by 2-hydroxyflutamide. At a time when individual susceptibility to adverse drug reactions is not fully understood, this study provides evidence that inter-individual variation in mitochondrial genotype could be a factor in determining sensitivity to mitochondrial toxicants associated with costly adverse drug reactions.
Highlights
Drug-induced mitochondrial dysfunction is a major pathway associated with adverse drug reactions which has led to the withdrawal of therapeutic compounds from the market (Massart et al 2018)
Haplogroup J platelets had significantly lower complex I-driven respiration both when untreated and when treated with 250 μM 2-hydroxyflutamide. This was reflected in the EC50 for complex I-driven respiration in haplogroup J platelets, which was significantly less than the remaining haplogroups (Table 1)
The abundance of mitochondrial DNA (mtDNA) and absence of nuclear DNA in platelets makes these cell fragments an attractive model to study the effect of mtDNA variation upon mitochondrial function
Summary
Drug-induced mitochondrial dysfunction is a major pathway associated with adverse drug reactions which has led to the withdrawal of therapeutic compounds from the market (Massart et al 2018). Several studies have indicated that the mitochondrial genome may be a factor in the onset of adverse drug reactions, including those associated with linezolid and streptomycin (Chen et al 2007; Pacheu-Grau et al 2012; Penman et al 2020). Research to elucidate the triad of the mitochondrial genome, drug-induced mitochondrial dysfunction and adverse drug reactions is limited. This is due, in-part, to current screening tools which neglect the inter-individual genetic diversity present at the population level (Will and Dykens 2014). Research is required to define the potential importance of mitochondrial genetics in defining individual susceptibility to adverse drug reactions, as well as to provide the practical models required for the field to advance. The anucleate nature of platelets enables the effect of mtDNA variation to be determined without interference from the nuclear genome (Thon and Italiano 2012)
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