Li Huihui,Cui Yanmei,Hu Yule,Zhao Mengran,Li Kuanyu,Pang Xiaoyun,Sun Fei,Zhou Bing
Iron is a potent biochemical, and accurate homeostatic control is orchestrated by a network of interacting players at multiple levels. Although our understanding of organismal iron homeostasis has advanced, intracellular iron homeostasis is poorly understood, including coordination between organelles and iron export into the ER/Golgi. Here, we show that SLC39A13 (ZIP13), previously identified as a zinc transporter, promotes intracellular iron transport and reduces intracellular iron levels. ZIP13 loss causes an iron deficiency in the ER/Golgi and other intracellular compartments, such as lysosomes and mitochondria, as well as elevating iron in the cytosol. ZIP13 overexpression has the opposite effect, increasing iron in organellar compartments. We suggest that ZIP13 gatekeeps an iron trafficking route that shunts iron from the cytosol to the ER/Golgi hub. Zip13- knockout male mice have iron deposition in several tissues. These data demonstrate that mammalian ZIP13 is crucial for iron homeostasis and suggest a potential iron transport function.
Shanshan Guo,Yalin Wang,Binyu Lu,Yu Zhang,David M. Frazer,Bing Zhou
Liver fibrosis, driven by excessive collagen synthesis following hepatic injury, poses a significant health challenge. SLC39A13/ZIP13, a recently characterized intracellular iron transporter, is shown to provide iron to the ER/Golgi to help catalyze procollagen hydroxylation during collagen maturation. Here, we investigate whether ZIP13 plays a role during hepatic fibrogenesis modeled by CCl 4 stress or other inducers. ZIP13 expression is induced during liver fibrosis. Germline disruption of Zip13 dramatically reduces fibrosis. Surprisingly, these mice do not benefit from ZIP13 loss after CCl 4 challenge; instead, they are more susceptible to CCl 4 toxicity even with substantially less fibrosis development. This elevated vulnerability turns out to be a consequence of ferroptosis in the hepatocyte due to increased cytosolic iron after ZIP13 loss. Tissue-specific knockout (KO) reveals that hepatic stellate cell (HSC) KO of Zip13 attenuates liver fibrosis progression without adverse effects. Leveraging these findings, HSC-targeted delivery of Zip13 -siRNA demonstrates robust efficacy and safety in preclinical fibrosis models. These results provide critical insights into the complex role of iron in liver fibrosis, and indicate that targeting iron homeostasis via ZIP13 in the HSC may be effective to mitigate fibrogenesis by simultaneously suppressing the synthesis of multiple kinds of collagen while minimizing possible side effects.
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