Inhibition of arachidonic acid‐induced ER stress and mitochondrial dysfunction by novel dithiolethiones

Abstract

The mitochondrial respiratory chain is a major source of reactive oxygen species (ROS) under pathological conditions. Generation of ROS can induce ER stress, and may lead to apoptosis. This study investigated whether arachidonic acid (AA), a representative proinflammatory ω‐6 fatty acid, causes ROS‐mediated mitochondrial impairment and ER stress, and if so, whether a new dithiolethione compounds (DTTs) protect cells from AA‐induced apoptosis. In HepG2 cells, DTTs inhibited ER expansion induced by AA. Moreover, DTT treatment abrogated Grp78 and CHOP induction in AA‐treated cells. Inhibition of AA‐induced ER stress by the agents was responsible for the decrease in apoptosis. DTTs effectively inhibited mitochondrial permeability transition promoted by AA in combination with Fe++, thereby protecting cells from ROS‐induced apoptosis. It appeared that AMPK activation by DTTs contributed to cell survival effects, which was partly supported by the reversal of DTTs's restoration of mitochondrial membrane potential by concomitant compound C treatment. As a same token, AICAR, an AMPK activator, inhibited AA + Fe++‐induced mitochondrial permeability transition with an increase in cell viability. Our data support the conclusion that new DTT compounds were capable of protecting cells from AA‐induced ER stress, ROS production, and mitochondrial dysfunction, which might be associated with AMPK activation.