STF-083010 is an inhibitor of endonuclease activity of inositol requiring-enzyme 1α (IRE1α) that is involved in activation of IRE1α-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 SH-SY5Y 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 (ΔΨm) that could be a result of decreased mitochondrial substrate level phosphorylation. Finally, increased sensitivity of ΔΨm 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 IRE1α that is involved in activation of IRE1α-XBP1 axis of the unfolded protein response after ER stress. The impact of STF-083010 on mitochondrial functions could be associated with its possible off-target effect.

STF-083010 是肌醇需要酶 1α (IRE1α) 的核酸内切酶活性抑制剂，参与 ER 应激后未折叠蛋白反应的 IRE1α-XBP1 轴的激活。在之前的一些研究中，STF-083010 作为一种可能的抗肿瘤药物进行了测试，显示出能够诱导肿瘤细胞死亡或增加肿瘤细胞对其他肿瘤药物的敏感性。STF-083010 在不同的肝损伤和脂肪性肝炎模型中也表现出保肝作用。我们已经证明，STF-083010 对线粒体功能具有显着影响，且不依赖于 STF-083010 的应用方式。我们观察到，在 SH-SY5Y 细胞与 STF-083010 一起孵育或直接将 STF-083010 添加到呼吸中后，STF-083010 最大呼吸（代表线粒体呼吸链的最大电子传递能力）和备用呼吸能力均下降中等的。此外，我们还记录了 STF-083010 对线粒体膜电位 (ΔΨm) 产生的影响，这可能是线粒体底物水平磷酸化降低的结果。最后，记录了在 STF-083010 存在的情况下 ΔΨm 对解偶联剂的敏感性增加。我们的结果表明，STF-083010 对线粒体功能具有重要影响，独立于其抑制 IRE1α 核酸内切酶活性的能力，IRE1α 参与 ER 应激后未折叠蛋白响应的 IRE1α-XBP1 轴的激活。STF-083010 对线粒体功能的影响可能与其可能的脱靶效应有关。