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.

Assessment of the impact of mitochondrial genotype upon drug-induced mitochondrial dysfunction in platelets derived from healthy volunteers

“…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 ). In addition, drug-induced mitochondrial dysfunction is an important part of preclinical screening in the pharmaceutical industry.…”

Mitochondria as the Target of Hepatotoxicity and Drug-Induced Liver Injury: Molecular Mechanisms and Detection Methods

“…There is a large inter-individual variation in mtDNA copy number, and while the origin of this variation is still unknown, low mtDNA levels could present a risk factor for the mitochondrial toxicity of drugs known to interfere with mtDNA [ 6 ]. In addition, variations and mutations in mtDNA represent an important inter-individual difference associated with adverse drug reactions and idiosyncratic DILI [ 158 , 159 ]. Emerging studies have shown that mitochondrial genetics and specific mtDNA haplogroups are involved in increased susceptibility to drug toxicity, especially for toxicity induced by antibiotics, antiretrovirals and chemotherapeutic agents [ 159 ].…”

“…In addition, variations and mutations in mtDNA represent an important inter-individual difference associated with adverse drug reactions and idiosyncratic DILI [ 158 , 159 ]. Emerging studies have shown that mitochondrial genetics and specific mtDNA haplogroups are involved in increased susceptibility to drug toxicity, especially for toxicity induced by antibiotics, antiretrovirals and chemotherapeutic agents [ 159 ].…”

The frequency of the known mitochondrial variants associated with drug-induced toxicity in a Korean population

“…Limited information, however, is available about the roles of mitochondrial haplogroups in susceptibility to drug-induced toxicity. Anti-retroviral therapy (ART), antibiotics and chemotherapeutic agents are well known drug classes in relation to the mitochondria mediated drug toxicities [ 7 ]. The mtDNA mutations and copy numbers have been proposed as potential biomarkers to monitor therapeutic responses and prognosis in cancer treatments, although the mechanisms are not well established [ 8 , 9 ].…”