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JNK Activation and Translocation to Mitochondria Mediates Mitochondrial Dysfunction and Cell Death Induced by VDAC Opening and Sorafenib in Hepatocarcinoma Cells

JNK Activation and Translocation to Mitochondria Mediates Mitochondrial Dysfunction and Cell Death Induced by VDAC Opening and Sorafenib in Hepatocarcinoma Cells

K A Heslop, A Rovini, E G Hunt, D Fang, M E Morris, C F Christie, M B Gooz, D N DeHart, Y Dang, J J Lemasters, E N Maldonado

Biochem Pharmacol. 2020 Jan;171:113728.

PMID: 31759978

Abstract:

The multikinase inhibitor sorafenib, and opening of voltage dependent anion channels (VDAC) by the erastin-like compound X1 promotes oxidative stress and mitochondrial dysfunction in hepatocarcinoma cells. Here, we hypothesized that X1 and sorafenib induce mitochondrial dysfunction by increasing reactive oxygen species (ROS) formation and activating c-Jun N-terminal kinases (JNKs), leading to translocation of activated JNK to mitochondria. Both X1 and sorafenib increased production of ROS and activated JNK. X1 and sorafenib caused a drop in mitochondrial membrane potential (ΔΨ), a readout of mitochondrial metabolism, after 60 min. Mitochondrial depolarization after X1 and sorafenib occurred in parallel with JNK activation, increased superoxide (O2•-) production, decreased basal and oligomycin sensitive respiration, and decreased maximal respiratory capacity. Increased production of O2•- after X1 or sorafenib was abrogated by JNK inhibition and antioxidants. S3QEL 2, a specific inhibitor of site IIIQo, at Complex III, prevented depolarization induced by X1. JNK inhibition by JNK inhibitors VIII and SP600125 also prevented mitochondrial depolarization. After X1, activated JNK translocated to mitochondria as assessed by proximity ligation assays. Tat-Sab KIM1, a peptide selectively preventing the binding of JNK to the outer mitochondrial membrane protein Sab, blocked the depolarization induced by X1 and sorafenib. X1 promoted cell death mostly by necroptosis that was partially prevented by JNK inhibition. These results indicate that JNK activation and translocation to mitochondria is a common mechanism of mitochondrial dysfunction induced by both VDAC opening and sorafenib.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP890888127	S3QEL 2		890888-12-7	Price

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