In order to clarify the mitochondrial toxicity mechanism of the organic arsenical MOPIMP (2-methoxy-4-(((4-(oxoarsanyl) phenyl) imino) methyl) phenol), research was carried out at the sub-cell level based on the previous finding that the compound MOPIMP can damage the mitochondria by triggering a burst of ROS. After investigating its influence on isolated mitochondria in vitro, it was demonstrated that a high dose of MOPIMP with short-term exposure can induce mitochondrial swelling, decrease the membrane potential, enhance the permeability of H⁺ and K⁺, and induce membrane lipid peroxidation, indicating that it can result in an MPT process in a ROS-mediated and Ca²⁺-independent manner. Additionally, MPT was also aggravated as a result of impairment of the membrane integrity and membrane fluidity. In addition, short-term incubation between mitochondria and compound MOPIMP promoted the inhibition of respiratory chain complexes I, II, III and IV, as well as damage to the respiration process, which supported the previous finding about the burst of ROS. On the other hand, after long-term exposure by the organic arsenical MOPIMP, mitochondrial metabolic dysfunction was triggered, which was in accordance with perturbation of the respiratory chain complexes as well as the respiration process. This work systematically sheds light on the mitochondrial toxicity mechanism of the organic arsenical MOPIMP, including induction of the MPT process and inhibition of respiratory metabolism, which provides a potential target for organic arsenicals as anti-tumor drugs.

中文翻译：

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有机砷的线粒体毒性：膜通透性转换孔张开和呼吸功能障碍†

为阐明有机砷MOPIMP（2-甲氧基-4-（（（4-（氧代arsanyl）苯基）亚氨基）甲基）苯酚）的线粒体毒性机制，在亚细胞水平进行了基于先前发现化合物MOPIMP可以通过触发ROS爆发来破坏线粒体。在体外研究其对离体线粒体的影响后，表明短期暴露大剂量MOPIMP可诱导线粒体肿胀，降低膜电位，增强H ⁺和K ⁺的通透性，并诱导膜脂过氧化，表明它可以在 ROS 介导和 Ca ^{2+中导致 MPT 过程}- 独立的方式。此外，由于膜完整性和膜流动性受损，MPT也加重。此外，线粒体与化合物MOPIMP之间的短期孵育促进了呼吸链复合物 I、II、III 和 IV 的抑制，以及对呼吸过程的损害，这支持了之前关于 ROS 爆发的发现。另一方面，有机砷MOPIMP长期暴露后，引发线粒体代谢功能障碍，这与呼吸链复合物的扰动以及呼吸过程有关。这项工作系统地揭示了有机砷MOPIMP的线粒体毒性机制，包括诱导 MPT 过程和抑制呼吸代谢，这为有机砷作为抗肿瘤药物提供了潜在的靶点。