VPS41-mediated incomplete autophagy aggravates cadmium-induced apoptosis in mouse hepatocytes.

Tao Wang, Lianqi Yan, Li Wang, Jian Sun, Huayi Qu, Yonggang Ma, Ruilong Song, Xishuai Tong, Jiaqiao Zhu, Yan Yuan, Jianhong Gu, Jianchun Bian, Zongping Liu, Hui Zou

Journal of hazardous materials 2023 Oct 05

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Exposure to cadmium (Cd), an environmental heavy metal contaminant, is a serious threat to global health that increases the burden of liver diseases. Autophagy and apoptosis are important in Cd-induced liver injury. However, the regulatory mechanisms involved in the progression of Cd-induced liver damage are poorly understood. Herein, we investigated the role of vacuolar protein sorting 41 (VPS41) in Cd-induced autophagy and apoptosis in hepatocytes. We used targeted VPS41 regulation to elucidate the mechanism of Cd-induced hepatotoxicity. Our data showed that Cd triggered incomplete autophagy by downregulating VPS41, aggravating Cd-induced hepatocyte apoptosis. Mechanistically, Cd-induced VPS41 downregulation interfered with the mTORC1-TFEB/TFE3 axis, leading to an imbalance in autophagy initiation and termination and abnormal activation of autophagy. Moreover, Cd-induced downregulation of VPS41 inhibited autophagosome-lysosome fusion, leading to blocked autophagic flux. This triggers incomplete autophagy, which causes excessive P62 accumulation, accelerating Caspase-9 (CASP9) cleavage. Incomplete autophagy blocks clearance of cleaved CASP9 (CL-CASP9) via the autophagic pathway, promoting apoptosis. Notably, VPS41 overexpression alleviated Cd-induced incomplete autophagy and apoptosis, independent of the homotypic fusion and protein sorting complex. This study provides a new mechanistic understanding of the relationship between autophagy and apoptosis, suggesting that VPS41 is a new therapeutic target for Cd-induced liver damage. Copyright © 2023 Elsevier B.V. All rights reserved.

Citation

Tao Wang, Lianqi Yan, Li Wang, Jian Sun, Huayi Qu, Yonggang Ma, Ruilong Song, Xishuai Tong, Jiaqiao Zhu, Yan Yuan, Jianhong Gu, Jianchun Bian, Zongping Liu, Hui Zou. VPS41-mediated incomplete autophagy aggravates cadmium-induced apoptosis in mouse hepatocytes. Journal of hazardous materials. 2023 Oct 05;459:132243