Shiga toxin 2 A-subunit induces mitochondrial damage, mitophagy and apoptosis via the interaction of Tom20 in Caco-2 cells

Jie Tang; Xiaoxue Lu; Tao Zhang; Yuyang Feng; Qiaolin Xu; Jing Li; Yuanzhi Lan; Huaxing Luo; Linghai Zeng; Yuanyuan Xiang; Yan Zhang; Qian Li; Xuhu Mao; Bin Tang; Dongzhu Zeng

doi:10.1016/j.heliyon.2023.e20012

Shiga toxin 2 A-subunit induces mitochondrial damage, mitophagy and apoptosis via the interaction of Tom20 in Caco-2 cells

Heliyon. 2023 Sep 9;9(9):e20012. doi: 10.1016/j.heliyon.2023.e20012. eCollection 2023 Sep.

Authors

Jie Tang¹, Xiaoxue Lu², Tao Zhang¹, Yuyang Feng², Qiaolin Xu¹, Jing Li¹, Yuanzhi Lan¹, Huaxing Luo¹, Linghai Zeng¹, Yuanyuan Xiang¹, Yan Zhang¹, Qian Li², Xuhu Mao², Bin Tang³, Dongzhu Zeng¹

Affiliations

¹ Department of General Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
² Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
³ Department of Clinical Laboratory, Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, Jiangjin, Chongqing, 402260, China.

Abstract

Shiga toxin type 2 (Stx2) is the primary virulence factor produced by Shiga toxin-producing enterohemorrhagic Escherichia coli (STEC), which causes epidemic outbreaks of gastrointestinal sickness and potentially fatal sequela hemolytic uremic syndrome (HUS). Most studies on Stx2-induced apoptosis have been performed with holotoxins, but the mechanism of how the A and B subunits of Stx2 cause apoptosis in cells is not clear. Here, we found that Stx2 A-subunit (Stx2A) induced mitochondrial damage, PINK1/Parkin-dependent mitophagy and apoptosis in Caco-2 cells. PINK1/Parkin-dependent mitophagy caused by Stx2A reduced apoptosis by decreasing the accumulation of reactive oxidative species (ROS). Mechanistically, Stx2A interacts with Tom20 on mitochondria to initiate the translocation of Bax to mitochondria, leading to mitochondrial damage and apoptosis. Overall, these data suggested that Stx2A induces mitochondrial damage, mitophagy and apoptosis via the interaction of Tom20 in Caco-2 cells and that mitophagy caused by Stx2A ameliorates apoptosis by eliminating damaged mitochondria. These findings provide evidence for the potential use of Tom20 inhibition as an anti-Shiga toxin therapy.

Keywords: Apoptosis; Mitophagy; Shiga toxin; Shiga toxin type 2; Tom20.