Emodin‐Induced Oxidative Inhibition of Mitochondrial Function Assists BiP/IRE1α/CHOP Signaling‐Mediated ER‐Related Apoptosis

Abstract

Cassiae Semen is a widely used herbal medicine and a popular edible variety in many dietary or health beverage. Emerging evidence disclosed that improper administration of Cassiae Semen could induce obvious liver injury, which is possibly attributed to emodin, one of the bioactive anthraquinone compounds in Cassiae Semen, which caused hepatotoxicity, but the underlying mechanisms are not completely understood. Hence, the present study firstly explored the possible role of oxidative stress-mediated mitochondrial dysfunction and ER stress in emodin-cause apoptosis of L02 cells, aiming to elaborate possible toxic mechanisms involved in emodin-induced hepatotoxicity. Our results showed that emodin-induced ROS activated ER stress and the UPR via the BiP/IRE1α/CHOP signaling pathway, followed by ER Ca2+ release and cytoplasmic Ca2+ overloading. At the same time, emodin-caused redox imbalance increased mtROS while decreased MMP and mitochondrial function, resulting in the leaks of mitochondrial-related proapoptotic factors. Interestingly, blocking Ca2+ release from ER by 2-APB could inhibit emodin-induced apoptosis of L02, but the restored mitochondrial function did not reduce the apoptosis rates of emodin-treated cells. Besides, tunicamycin (TM) and doxorubicin (DOX) were used to activate ER stress and mitochondrial injury at a dosage where obvious apoptosis was not observed, respectively. We found that cotreatment with TM and DOX significantly induced apoptosis of L02 cells. Thus, all the results indicated that emodin-induced excessive ROS generation and redox imbalance promoted apoptosis, which was mainly associated with BiP/IRE1α/CHOP signaling-mediated ER stress and would be enhanced by oxidative stress-mediated mitochondrial dysfunction. Altogether, this finding has implicated that redox imbalance-mediated ER stress could be an alternative target for the treatment of Cassiae Semen or other medicine-food homologous varieties containing emodin-induced liver injury.

IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis

“…Emodin-induced excessive ROS generation and redox imbalance promoted apoptosis, which was mainly associated with BiP/IRE1α/CHOP signaling-mediated ER stress and would be enhanced by oxidative stress-mediated mitochondrial dysfunction (Qiu et al, 2021) Pulmonary artery smooth muscle cells IRE1-XBP1 signaling way IRE1α-XBP1 pathway is involved in the process of hypoxia-induced pulmonary vascular remodeling; 4u8c could restrain hypoxia-induced cell proliferation and migration and reverse the hypoxia-induced apoptosis arrest, while quercetin excited excessive ERS and the IRE1 pathway in hypoxic PASMCs and promoted apoptosis (Cao et al, 2019) SH-SY5Y cell IRE1-MAMs signaling way Aβ peptides enhance cytotoxicity and mitochondrial damage in SH-SY5Y cells by targeting MAMs (Chu et al, 2021) Mouse liver cell IRE1-MAMs signaling way IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions (Carreras-Sureda et al, 2019) Abbreviations: IRE1, inositol-requiring enzyme 1; RIDD, regulated IRE1-dependent decay; ROS, reactive oxygen species.…”

Emodin disrupts the Notch1/Nrf2/GPX4 antioxidant system and promotes renal cell ferroptosis

“…It has been reported that emodin‐induced toxicity is correlated with glutathione (GSH) depletion and elevation of reactive oxygen species (ROS) (Huang et al, 2019; Qiu et al, 2021). Oxidative stress is defined by an imbalance between excessive ROS content and reduced activity of antioxidant mechanisms (Xie et al, 2016).…”

Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α

“…Given that the relationship between ER stress and DOX-induced cardiotoxicity has not been widely explored [ 28 , 29 ], we examined the role of an anti-ER stress chemical chaperone, tauroursodeoxycholic acid (TUDCA) in DOX-induced cardiomyopathy (Supplementary Fig. 14a ).…”