Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

Abstract

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 speciesmediated 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. 2 A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 2. Main features of the mitochondria 2.1. Structure and main components Mitochondria, whose size is ~1 µm, are intracellular organelles with two membranes (namely the outer and the inner membrane) that surround the matrix. This compartment contains numerous enzymes involved in different key oxidative pathways such as mitochondrial fatty acid oxidation (mtFAO) and pyruvate oxidation via the tricarboxylic acid (TCA) cycle. The matrix also contains the mitochondrial DNA (mtDNA) and all the components (e.g. enzymes and transcription factors) mandatory for its replication, transcription, translation and repair. However, this small genome allows only the synthesis of 13 polypeptides of the mitochondrial respiratory chain (MRC), whereas all other mitochondrial proteins (~1700) are encoded by the nuclear DNA and targeted to mitochondria (Area-Gomez and Schon, 2014; Borst and Grivell, 1981). Notably, mitochondria share different major features with bacteria including size, double-membrane structure, mode of mtDNA transcription and some components of the mtDNA translation machinery (Santini et al., 2017; Schon and Fromenty, 2015). These features are due to the fact that the precursors of mitochondria were bacteria that became endosymbiotic residents of "proto-eukaryotic" cells early in our evolutionary history (Pessayre et al., 2010). 2.2. Production of energy One major role of mitochondria is the production of energy so that these organelles...

Elevated cAMP Protects against Diclofenac-Induced Toxicity in Primary Rat Hepatocytes: A Protective Effect Mediated by the Exchange Protein Directly Activated by cAMP/cAMP-Regulated Guanine Nucleotide Exchange Factors

“…As in our studies, EPAC2A was barely detectable; the observed protective effects of EPAC2 inhibition can be primarily attributed to EPAC2B, which is also localized at the mitochondria. Another explanation may be that under stress conditions such as DILI, EPAC2A expression may be induced due to changes in the methylation status of the gene (Gervin et al, 2017;Fromenty, 2020). Further studies on the differential expression and subsequent impact of EPAC proteins on functional responses in primary rat hepatocytes will be fascinating but are beyond the current manuscript's scope.…”

“…If EPAC2A is low or absent in hepatocytes, this implies that the observed protective effects of EPAC2 can be attributed to EPAC2B which is also localized at the mitochondria. Another probable explanation is that under stress conditions such as DILI, EPAC2A expression may be induced due to changes in the methylation status of the gene (Gervin et al, 2017;Fromenty, 2020).…”

Cytochrome P450 2E1 should not be neglected for acetaminophen-induced liver injury in metabolic diseases with altered insulin levels or glucose homeostasis

“…Although there are still some uncertainties regarding the precise mechanisms whereby APAP overdose can induce liver injury, numerous studies pointed to a major role of cytochrome P450 2E1 (CYP2E1), at least in mice [2,6,7]. Indeed, this enzyme catalyzes the oxidation of APAP to Nacetyl-p-benzoquinone imine (NAPQI), a highly reactive metabolite inducing severe mitochondrial dysfunction at the respiratory chain level, overproduction of reactive oxygen species (ROS), c-jun N-terminal kinase (JNK) activation, mitochondrial permeability transition, ATP depletion and massive hepatocellular necrosis [8,9]. In human, CYP3A4 might be an important enzyme catalyzing NAPQI generation in addition to CYP2E1 [2,10].…”

Treatments in Covid-19 patients with pre-existing metabolic dysfunction-associated fatty liver disease: A potential threat for drug-induced liver injury?

“…Many drugs can impair mtFAO by different mechanisms including direct inhibition of mtFAO enzymes such as carnitine palmitoyltransferase 1 (CPT1) and different acyl-CoA dehydrogenases as well as direct impairment of MRC and OXPHOS [ 20 , 63 , 77 , 78 ]. OXPHOS can also be impaired indirectly by alteration of mitochondrial DNA (mtDNA) homeostasis such as inhibition of mtDNA replication or translation [ 20 , 77 , 79 ]. All these adverse effects are not mutually exclusive.…”

“…For instance, some drugs such as acetaminophen, amiodarone and tamoxifen can directly inhibit both mtFAO and MRC [ 20 , 77 , 78 ]. In addition, acetaminophen and troglitazone can impair MRC activity directly or indirectly through mtDNA depletion [ 77 , 79 ]. Finally, it should be mentioned that drug-induced inhibition of mtFAO could not only worsen pre-existing steatosis but also necrosis since this metabolic pathway is a major source of energy in hepatocytes [ 77 , 80 ].…”