Role of JNK Translocation to Mitochondria Leading to Inhibition of Mitochondria Bioenergetics in Acetaminophen-induced Liver Injury

Inhibitory effects of Schisandra chinensis on acetaminophen-induced hepatotoxicity

“…Activation of hepatic JNK is recognized as a key event in the progression and exacerbation of acetaminophen toxicity, and inhibition of p-JNK has been shown to protect mice against acetaminophen-induced hepatotoxicity (28,29). In the present study, Schisandra chinensis was found to inhibit p-JNK expression levels compared with those in the acetaminophen-treated hepatocytes…”

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

“…An early consequence of APAP-induced mitochondrial oxidative/nitrosative stress is activation of c-jun N -terminal kinase (JNK) in the cytosol, the prevention of which by anti-oxidants in vivo confirms its dependence on mitochondrial free radical generation [33, 41]. JNK activation is an early event after APAP overdose, occurring in the cytosol within 1 hour of treatment of mice with 300mg/kg APAP [42] and seems to be influenced by the apoptosis signal-regulating kinase 1 (ASK1) since mice lacking ASK1 were protected against APAP-induced JNK activation [43].…”

“…Since activation of ASK1 requires oxidation and detachment of its binding partner thioredoxin 1 [44], this could be the mechanistic interface between mitochondrial oxidant stress and ASK 1 activation, since thioredoxin oxidation occurs within mitochondria after APAP overdose in vivo [45] and activities of thioredoxin 1 & 2 have been shown to be modified by NAPQI [44]. In addition, the mixed-lineage kinase 3 (MLK3) is also activated by oxidant stress during APAP hepatotoxicity in vivo [46] which, along with ASK1, phosphorylates JNK through the MAPK2 kinase MKK4 [33, 41, 47]. Phosphorylation and activation of JNK within the cytosol subsequently results in its translocation to the mitochondria [41] by binding to a docking protein Sab on the outer mitochondrial membrane [48].…”

“…In addition, the mixed-lineage kinase 3 (MLK3) is also activated by oxidant stress during APAP hepatotoxicity in vivo [46] which, along with ASK1, phosphorylates JNK through the MAPK2 kinase MKK4 [33, 41, 47]. Phosphorylation and activation of JNK within the cytosol subsequently results in its translocation to the mitochondria [41] by binding to a docking protein Sab on the outer mitochondrial membrane [48]. The binding to and phosphorylation of Sab by p-JNK on the outer mitochondrial membrane leads to release of protein tyrosine phosphatase nonreceptor type 6 (SHP1) from Sab in the inside of the mitochondrial outer membrane and subsequent decrease in mitochondrial respiration [49] and amplification of oxygen free radical and peroxynitrite formation [33].…”

Highlight report: acetaminophen hepatotoxicity

“…APAP is known to be metabolically activated to the reactive N-acetyl-p-benzoquinone imine (NAPQI), which forms protein adducts including mitochondrial proteins leading to mitochondrial oxidative stress (Ramachandran et al 2013;Cohen et al 1997). As a consequence c-jun N-terminal kinase is translocated to the mitochondria, which enhances generation of reactive oxygen species (Ramachandran et al 2013;Hanawa et al 2008;Saito et al 2010). This may lead to opening of the mitochondrial membrane transition pore and cause a form of cell death which differs from classical apoptosis and has been named 'necroptosis' (Kon et al 2004;Gujral et al 2002;Ni et al 2012).…”