Chongqing, China
Chongqing, China

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Pi H.,Chongqing Medical University | Xu S.,Chongqing Medical University | Zhang L.,Chongqing Medical University | Guo P.,Chongqing Medical University | And 12 more authors.
Autophagy | Year: 2013

How cadmium (cd) induces mitochondrial loss in the context of its hepatotoxic effects remains enigmatic. The purpose of the study was to investigate whether mitophagy contributes to mitochondrial loss in cadmium-induced hepatotoxicity and to determine the potential mechanism. in normal human liver L02 cells, we observed that cd treatment led to a significant increase in Lc3-ii formation, the number of GFP-Lc3 puncta and lysosomal colocalization with mitochondria. These results were associated with mitochondrial loss and bioenergetic deficit. Additionally, the abrogation of excessive mitophagy by ATG5 siRNA treatment efficiently suppressed the mitochondrial loss and cytotoxicity of cd. Before overactivating mitophagy, cd induced excessive mitochondrial fragmentation as a result of increasing dynamin 1-like (DNM1L) expression and enhancing the DNM1L mitochondrial translocation. Moreover, reversing the excessive mitochondrial fragmentation via the administration of DNM1L siRNA significantly inhibited the observed overactivation of mitophagy in cd-induced hepatotoxicity. Notably, the selective DNM1L inhibitor Mdivi-1 blocked abnormal mitophagy and subsequently ameliorated cd-induced hepatotoxicity in vivo. Together, our data indicated that cd induces mitochondrial loss via the overactivation of mitophagy following DNM1L-dependent mitochondrial fragmentation. The balanced activity of DNM1L and mitophagy signaling may be a potential therapeutic approach to treat cd-induced hepatotoxicity. © 2013 Landes Bioscience.


Qiu J.,Bioengineering College | Wang G.,Bioengineering College | Hu J.,Bioengineering College | Peng Q.,Bioengineering College | Zheng Y.,Bioengineering College
Molecular and Cellular Biochemistry | Year: 2011

The Id1 protein is critical for endothelial cell angiogenesis, and this function is particularly relevant to cancer development, cardiovascular disease, and wound healing. We hypothesized that Id1 enhanced migration and tubulogenesis by controlling the expression and function of p53. In this study, we examined cell migration following Id1 overexpression and silencing endothelial cells. The results showed that overexpression of Id1 enhanced cell migration and increased beta1-integrin expression, but inhibition of beta1-integrin blocked motility even in clones overexpressing Id1, suggesting that Id1 regulated motility through beta1-integrin. Further analysis revealed that p53, whose expression and distribution is regulated by Id1, was critical for cell migration, and may be involved in regulating the expression of beta1-integrin. Inhibiting p53 function using PFT-α, a functional inhibitor of p53, increased the expression of beta1-integrin and promoted cell migration even in Id1-silencing endothelial cells, demonstrating that the Id1 knockdowns induced inhibition of endothelial cell migration and the expression of beta1-integrin were controlled by p53. In addition, Id1-p53 pathway regulated the cytoskeleton formation and tubulogenesis. These results demonstrate that Id1-induced beta1-integrin expression in endothelial cells and the function of Id1 in cell migration and tubulogenesis are dependent on p53. © Springer Science+Business Media, LLC. 2011.

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