Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Slovak Republic.
Department of Medical Biochemistry JFM CU, JFM CU Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Slovak Republic.
Toxicol In Vitro. 2023 Oct;92:105652. doi: 10.1016/j.tiv.2023.105652. Epub 2023 Jul 21.
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 是一种肌醇需求酶 1α（IRE1α）内切核酸酶活性抑制剂，参与内质网应激后未折叠蛋白反应中 IRE1α-XBP1 轴的激活。在一些先前的研究中，STF-083010 被测试为一种潜在的抗肿瘤药物，具有诱导肿瘤细胞死亡或增加肿瘤细胞对其他致瘤剂敏感性的能力。STF-083010 还在不同的肝损伤和脂肪性肝炎模型中表现出肝保护作用。我们已经表明，STF-083010 对线粒体功能有显著影响，而这种影响不依赖于 STF-083010 的应用方式。我们观察到，无论是在孵育 SH-SY5Y 细胞或直接向呼吸介质中添加 STF-083010 后，STF-083010 均会降低最大呼吸作用（代表线粒体呼吸链的最大电子传递能力）和备用呼吸能力。此外，我们记录了 STF-083010 对线粒体膜电位（ΔΨm）产生的影响，这可能是由于线粒体底物水平磷酸化减少所致。最后，我们记录了在 STF-083010 存在下，ΔΨm 对解偶联剂的敏感性增加。我们的结果表明，STF-083010 对线粒体功能有重要影响，而与其抑制内质网应激后未折叠蛋白反应中 IRE1α-XBP1 轴激活所涉及的 IRE1α 内切核酸酶活性的能力无关。STF-083010 对线粒体功能的影响可能与其可能的脱靶效应有关。
