期刊
TOXICOLOGY IN VITRO
卷 92, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2023.105652
关键词
Mitochondria; Respiration; Membrane potential; Endoplasmic reticulum
类别
STF-083010 is an inhibitor of IRE1α endonuclease activity, which is involved in the activation of IRE1α-XBP1 axis in the unfolded protein response after ER stress. It exhibits antitumor activity and increases the sensitivity of tumor cells to other neoplastic agents. Additionally, it has hepatoprotective effects in various models of liver injury and steatohepatitis. Our study reveals that STF-083010 has a significant impact on mitochondrial functions, which is not dependent on its ability to inhibit IRE1α endonuclease activity.
STF-083010 is an inhibitor of endonuclease activity of inositol requiring-enzyme 1 & alpha; (IRE1 & alpha;) that is involved in activation of IRE1 & alpha;-XBP1 axis of the unfolded protein response after ER stress. STF-083010 was tested as a possible antitumor agent in some previous studies exhibiting the ability either to induce death of tumour cells or to increase sensitivity of tumours cells to other neoplastic agents. STF-083010 exhibits also hepatoprotective effects in different models of liver injury and hepatic steatohepatitis. We have shown that STF-083010 has significant impact on mitochondrial functions that is not dependent on the way of STF-083010 application. We have observed that STF-083010 decrease of both maximal respiration (representing maximal electron transfer capacity of mitochondrial respiratory chain) and spare respiratory capacity after either incubation of the SHSY5Y cells with STF-083010 or direct addition of STF-083010 to the respiration medium. In addition, we have documented impact of STF-083010 on generation of mitochondrial membrane potential (& UDelta;& psi;m) that could be a result of decreased mitochondrial substrate level phosphorylation. Finally, increased sensitivity of & UDelta;& psi;m to uncoupler in the presence of STF-083010 was documented. Our results indicate that STF-083010 has important impact on mitochondrial functions independently of its ability to inhibit endonuclease activity of IRE1 & alpha; that is involved in activation of IRE1 & alpha;-XBP1 axis of the unfolded protein response after ER stress. The impact of STF083010 on mitochondrial functions could be associated with its possible off-target effect.
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