Sodium sulfite triggered hepatic apoptosis, necroptosis, and pyroptosis by inducing mitochondrial damage in mice and AML-12 cells

• Published in: Journal of hazardous materials 2024-04, Vol.467, p.133719, Article 133719
• Main Authors: Liu, Meitong, Lu, Jing, Hu, Jinpin, Chen, Yuelin, Deng, Xuming, Wang, Jianfeng, Zhang, Shengzhuo, Guo, Jiakang, Li, Weiru, Guan, Shuang
• Format: Article
• Language: English
• Subjects: Apoptosis; Necroptosis; p-MLKL; Pyroptosis; Sodium sulfite
• ISSN: 0304-3894; 1873-3336; 1873-3336
• DOI: 10.1016/j.jhazmat.2024.133719

Sodium sulfite (SS) is a biological derivative of the air pollutant sulfur dioxide, and is often used as a food and pharmaceutical additive. Improper or excessive SS exposure in liver cell death. The phenomenon of simultaneous regulation of apoptosis, necroptosis, and pyroptosis is defined as PANoptosis. However, the specific types of programmed cell death (PCD) caused by SS and their interconnections remain unclear. In the present study, C57BL/6 mice were orally administered SS for 30 d, consecutively, to establish an in vivo mouse exposure model. AML-12 cells were treated with SS for 24 h to establish an in vitro exposure model. The results showed that SS-induced mitochondrial reactive oxygen species (mtROS) accumulation activated the BAX/Bcl-2/caspase 3 pathway to trigger apoptosis and RIPK1/RIPK3/p-MLKL to trigger necroptosis. Interestingly, ROS-activated p-MLKL perforated not the cell membrane as well as the lysosomal membrane. We determined that p-MLKL mediates lysosomal membrane permeabilization (LMP), resulting in cathepsin B (CTSB) release. Furthermore, knockdown of MLKL, a CTSB inhibitor (CA074-ME) and an NLRP3 inhibitor (MCC950) alleviated SS-induced pyroptosis. In summary, our study showed that SS induced apoptosis and necroptosis though mtROS accumulation, whereas the activation of p-MLKL mediated NLRP3-dependent pyroptosis by causing CTSB leakage through LMP. This study comprehensively explored the mechanism unerlying SS-induced PCD and provided an experimental basis for p-MLKL as a potential regulatory protein in PANoptosis. [Display omitted] •Sodium sulfite (SS) induced apoptosis via BAX/Bcl-2/caspase 3 pathway in vivo and in vitro.•SS induced necroptosis via RIPK1/RIPK3/p-MLKL pathway in vivo and in vitro.•p-MLKL mediated SS-induced lysosomal membrane permeabilization.•p-MLKL mediated SS-induced NLRP3-dependent pyroptosis.