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.