Since numerous drugs are able to impair mitochondrial function (Labbe et?al

Since numerous drugs are able to impair mitochondrial function (Labbe et?al. translation of ATF4, a transcription factor which possesses a specific structure (uORF) on its mRNA. ATF4 then activates the synthesis of chaperones and proteins involved in autophagy, protein secretion, and amino acid metabolism. IRE1 possesses a kinase activity leading to its autophosphorylation and activation of a RNAse activity. This leads to the splicing of XBP1 mRNA, which is then translated into an active transcription factor. The transcription factor ATF6, which is bound to the ER membranes as an inactive precursor is transferred via COPII\coated vesicles to the Golgi apparatus, where it is cleaved by the S1P and S2P proteases into an active form. XBP1 and ATF6 will then activate in the nucleus the transcription of a set of factors allowing to restore ER homeostasis including chaperones, foldases, and proteins MBX-2982 involved in the degradation of unfolded polypeptides (ER\associated degradation). If these mechanisms are not efficient to restore ER and cell homeostasis, the UPR will eventually activate mechanisms leading to cell apoptosis, in particular via the transcription factor C/EBP homologous protein (CHOP). UPR activation involves three different effectors (also referred to as the 3 arms of the UPR): inositol requiring 1(IRE1(ATF6(PPARand investigations reported that APAP was also able to induce an ER stress and that such deleterious effect could play an significant role in APAP\induced cell death in liver, kidney, or inner ear (Lorz et?al. 2004; Nagy et?al. 2007, 2010; Uzi et?al. 2013; Kalinec SIR2L4 et?al. 2014). In one of these studies, mortality induced by a lethal dose of APAP (1?g/kg) was completely prevented in CHOP knockout mice but data regarding liver injury induced by a lower MBX-2982 dose of this painkiller (500?mg/kg) showed either a protection or no effect depending of the route of APAP administration (Uzi et?al. 2013). In addition, other studies dealing with APAP hepatotoxicity did not find markers of ER stress (Van Summeren et?al. 2011; Hur et?al. 2012; van Summeren et?al. 2013). Actually, some data in mice indicated that ER stress was a relatively late event after APAP intoxication (500?mg/kg), being significant only 12?hours following APAP MBX-2982 administration (Hur et?al. 2012; Uzi et?al. 2013). In contrast, mitochondrial alterations, ATP depletion, JNK activation, oxidative stress, and increased cytosolic calcium occurred much earlier in mouse liver after the same dose of APAP (Burcham and Harman 1988; Jaeschke 1990; Ruepp et?al. 2002; Aubert et?al. 2012; Hur et?al. 2012). Investigations in the human hepatoma HuH7 cell line also suggested that ER stress induced by APAP occurred well after mitochondrial alterations (Macanas\Pirard et?al. 2005). Thus, further studies are required to determine whether ER stress is a major pathway involved in APAP toxicity and cell death. The mechanism whereby APAP induces ER stress is poorly understood. A first hypothesis could be the occurrence of microsomal alterations secondary to NAPQI generation. Indeed, it has been reported that APAP MBX-2982 induced severe GSH depletion, lipid peroxidation, and an oxidative shift of the ER oxidoreductases ERp72 and PDI in liver microsomes (Nagy et?al. 2007; Letelier et?al. 2011). Furthermore, NAPQI can covalently bind to several microsomal proteins such as GSH\S\transferase, PDI, and calreticulin (Pumford et?al. 1990; Weis et?al. 1992; Zhou et?al. 1996; Shin et?al. 2007). Because PDI and calreticulin play a major role in protein folding and calcium sequestration within the ER (Coe and Michalak 2009), covalent binding of NAPQI to these proteins could induce an ER stress. Interestingly, it has been shown that other reactive benzoquinones induced an ER stress (Wang et?al. 2006). Second, ER stress might also be a secondary consequence of mitochondrial dysfunction, as discussed later on with other drugs such as arsenic trioxide and efavirenz. Amiodarone This broad\spectrum antiarrhythmic drug also presents an antianginal effect (Table?1). The main.