Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

Mitochondrial DNA (mtDNA) encodes for 13 proteins involved in the oxidative phosphorylation (OXPHOS) process. In liver, genetic or acquired impairment of mtDNA homeostasis can reduce ATP output but also decrease fatty acid oxidation, thus leading to different hepatic lesions including massive necrosis and microvesicular steatosis. Hence, a severe impairment of mtDNA homeostasis can lead to liver failure and death. An increasing number of investigations report that some drugs can induce mitochondrial dysfunction and drug-induced liver injury (DILI) by altering mtDNA homeostasis. Some drugs such as ciprofloxacin, antiretroviral nucleoside reverse-transcriptase inhibitors and tacrine can inhibit hepatic mtDNA replication, thus inducing mtDNA depletion. Drug-induced reduced mtDNA levels can also be the consequence of reactive oxygen species-mediated oxidative damage to mtDNA, which triggers its degradation by mitochondrial nucleases. Such mechanism is suspected for acetaminophen and troglitazone. Other pharmaceuticals such as linezolid and tetracyclines can impair mtDNA translation, thus selectively reducing the synthesis of the 13 mtDNA-encoded proteins. Lastly, some drugs might alter the mtDNA methylation status but the pathophysiological consequences of such alteration are still unclear. Drug-induced impairment of mtDNA homeostasis is probably under-recognized since preclinical and post-marketing safety studies do not classically investigate mtDNA levels, mitochondrial protein synthesis and mtDNA oxidative damage.