1. Gestational exposure to environmental cadmium induces placental apoptosis and fetal growth restriction via Parkin-modulated MCL-1 degradation.
- Author
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Zhu, Hua-Long, Dai, Li-Min, Xiong, Yong-Wei, Shi, Xue-Ting, Liu, Wei-Bo, Fu, Yi-Ting, Zhou, Guo-Xiang, Zhang, Shuang, Gao, Lan, Zhang, Cheng, Zhao, Ling-Li, Xu, Xiao-Feng, Huang, Yi-chao, Xu, De-Xiang, and Wang, Hua
- Subjects
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FETAL growth retardation , *PLACENTA , *POLLUTANTS , *ENVIRONMENTAL exposure , *CADMIUM , *PROTEOLYSIS , *APOPTOSIS - Abstract
Heavy metal cadmium (Cd), a classical environmental pollutant, causes placental apoptosis and fetal growth restriction (FGR), whereby the mechanism remains unclear. Here, our human case-control study firstly showed that there was a positive association of Parkin mitochondrial translocation, MCL-1 reduction, placental apoptosis, and all-cause FGR. Subsequently, Cd was administered to establish in vitro and in vivo models of placental apoptosis or FGR. Our models demonstrated that Parkin mitochondrial translocation was observed in Cd-administrated placental trophoblasts. Meaningfully, Parkin siRNA (siR) dramatically mitigated Cd-triggered apoptosis in placental trophoblasts. Mdivi-1 (M-1), an inhibitor for Parkin mitochondrial translocation, mitigated Cd-induced apoptosis in placental trophoblasts, which further ameliorated the effect of attenuated placental sizes in Cd-exposed mice. Furthermore, the interaction of MCL-1 with Parkin or Ub in Cd-stimulated cells was stronger than that in controls. MG132, an inhibitor for proteasome, abolished MCL-1 degradation in Cd-stimulated cells. Importantly, Parkin siR and M-1 memorably abolished the ubiquitin-dependent degradation of MCL-1 in placental trophoblasts. Interestingly, mito-TEMPO and melatonin, two mitochondria-targeted antioxidants, obviously rescued Cd-caused mitochondrial membrane potential (MMP) decrease, Parkin mitochondrial translocation, MCL-1 degradation, and apoptosis in placental trophoblasts. In conclusion, cadmium induces placental apoptosis and FGR via mtROS-mediated Parkin-modulated degradation of MCL-1. [Display omitted] • Parkin mitochondrial translocation and apoptosis occur in SGA placentae. • Cadmium promotes placental apoptosis via MCL-1 degradation. • Cadmium causes MCL-1 degradation by Parkin mitochondrial translocation. • Cadmium promotes Parkin mitochondrial translocation via mtROS release. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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