Mitochondrial (dys)function – a factor underlying the variability of efavirenz‐induced hepatotoxicity?

Abstract

BACKGROUND AND PURPOSEThe non-nucleoside analogue reverse transcriptase inhibitor efavirenz is associated with hepatic toxicity and metabolic disturbances. Although the mechanisms involved are not clear, recent evidence has pinpointed a specific mitochondrial action of efavirenz accompanied by the induction of an endoplasmic reticulum (ER) stress/unfolded protein response in human hepatic cells. The aim of this study was to further investigate the involvement of this organelle by evaluating efavirenz's effects in cells lacking functional mitochondria (rho°) and comparing them with those of the typical mitotoxic agent rotenone, a standard complex I inhibitor, and the ER stress inducer thapsigargin. EXPERIMENTAL APPROACH Hep3B rho+ and rho°cells were treated with clinically relevant concentrations of efavirenz, then mitochondrial function and cytotoxicity were studied using standard cell biology techniques. KEY RESULTSEfavirenz-treated rho°cells exhibited a substantial reduction in parameters indicative of mitochondrial interference, such as increased superoxide production, mitochondrial mass/morphology alterations and enhanced expression of LONP, a highly conserved mitochondrial protease. In line with these results, the cytotoxic effect (cell number, chromatin condensation, cell cycle alterations and induction of apoptosis) of efavirenz was less pronounced in Hep3B respiration-depleted cells than in wild-type cells. The effect of efavirenz was both similar and different from those of two distinct mitochondrial stressors, thapsigargin and rotenone. CONCLUSIONS AND IMPLICATIONSCells lacking normal mitochondria (rho°) are less vulnerable to efavirenz. Our results provide further evidence that the hepatic damage induced by efavirenz involves acute interference with mitochondria and extend our knowledge of the response of mitochondria/ER to a stress stimulus.

Combination of tenofovir and emtricitabine with efavirenz does not moderate inhibitory effect of efavirenz on mitochondrial function and cholesterol biosynthesis in human T lymphoblastoid cell line

“…Thus, EFV has several affections on mitochondria. In a study comparing Hep3B cells with functional mitochondria (rho+) and Hep3B cells lacking functional mitochondria (rho°), cells with functional mitochondria were more sensitive to the toxic effects of EFV (42).…”

Lon protease: a novel mitochondrial matrix protein in the interconnection between drug‐induced mitochondrial dysfunction and endoplasmic reticulum stress

“…The aim of this work was to compare mitochondrial/ER contact during combined ER/mitochondrial stress using an in vitro model and to establish whether Lon is involved in this interorganelle interaction. In previous publications (Apostolova et al, ; Polo et al, ), we have described an intriguing dual phenomenon of mitochondrial and ER‐stress in human hepatic cells treated with the antiretroviral drug efavirenz. This non‐nucleoside analogue reverse transcriptase (RT) inhibitor exerts a rapid, direct inhibitory effect on mitochondrial respiration, which leads to a decrease in mitochondrial membrane potential (ΔΨ m ) and enhanced ROS levels (Apostolova et al, ; Polo et al, ).…”

“…In previous publications (Apostolova et al, ; Polo et al, ), we have described an intriguing dual phenomenon of mitochondrial and ER‐stress in human hepatic cells treated with the antiretroviral drug efavirenz. This non‐nucleoside analogue reverse transcriptase (RT) inhibitor exerts a rapid, direct inhibitory effect on mitochondrial respiration, which leads to a decrease in mitochondrial membrane potential (ΔΨ m ) and enhanced ROS levels (Apostolova et al, ; Polo et al, ). Secondary to its mitochondrial action, efavirenz activates unfolded protein response (UPR) and produces ER‐stress (Apostolova et al, ).…”

“…Secondary to its mitochondrial action, efavirenz activates unfolded protein response (UPR) and produces ER‐stress (Apostolova et al, ). Moreover, this dual effect of efavirenz is associated with an up‐regulation of Lon expression, an effect that is diminished in cells with compromised mitochondrial respiration (Polo et al, ). Having previously analysed the mitochondrial effect of efavirenz, we now anticipated that mitochondrial dynamics might be altered and that the expression of fusion/fission proteins might be modified.…”

Efavirenz Induced Suicidal Death of Human Erythrocytes

“…Efavirenz has been shown to trigger apoptosis [41][42][43][44][45], an effect in part due to interference with mitochondrial potential and function [41,43,45].…”