Iron metabolism is essential for many cellular processes, including oxygen transport, respiration and DNA synthesis, and many cancer cells exhibit dysregulation in iron metabolism. Maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs), which control the expression of iron-related genes by binding iron-responsive elements (IREs) of target mRNAs. Here, we report that mitochondrial SIRT3 regulates cellular iron metabolism by modulating IRP1 activity. SIRT3 loss increases reactive oxygen species production, leading to elevated IRP1 binding to IREs. As a consequence, IRP1 target genes, such as the transferrin receptor (TfR1), a membrane-associated glycoprotein critical for iron uptake and cell proliferation, are controlled by SIRT3. Importantly, SIRT3 deficiency results in a defect in cellular iron homeostasis. SIRT3 null cells contain high levels of iron and lose iron-dependent TfR1 regulation. Moreover, SIRT3 null mice exhibit higher levels of iron and TfR1 expression in the pancreas. We found that the regulation of iron uptake and TfR1 expression contribute to the tumor-suppressive activity of SIRT3. Indeed, SIRT3 expression is negatively correlated with TfR1 expression in human pancreatic cancers. SIRT3 overexpression decreases TfR1 expression by inhibiting IRP1 and represses proliferation in pancreatic cancer cells. Our data uncover a novel role of SIRT3 in cellular iron metabolism through IRP1 regulation and suggest that SIRT3 functions as a tumor suppressor, in part, by modulating cellular iron metabolism.Oncogene advance online publication, 9 June 2014; doi:10.1038/onc.2014.124.
This research output has an Altmetric Attention Score of 6. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 27 May 2022.
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#71,069
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Outputs of similar age from Oncogene
#22
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Altmetric has tracked 33,949,960 research outputs across all sources so far. This one has received more attention than most of these and is in the 73rd percentile.
So far Altmetric has tracked 14,072 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.9. This one has gotten more attention than average, scoring higher than 55% of its peers.
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We're also able to compare this research output to 85 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 74% of its contemporaries.
