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. 2013 Mar 10;18(8):956–972. doi: 10.1089/ars.2012.4880

FIG. 2.

FIG. 2.

Interaction of gallium with cellular iron metabolism. The potential sites of gallium's interaction with cellular iron metabolism are identified in the bordered boxes. Membrane transport: TfR mediated. In the circulation, gallium(III) is transported and bound to Tf as Tf-Ga and is incorporated into TfR1-expressing cells by TfR1-mediated endocytosis of Tf-Ga complexes. Tf-Ga inhibits cellular iron incorporation by interfering with TfR-mediated uptake of Tf-Fe and the release of Fe from Tf within the endosome. Non-TfR mediated. Low-molecular-weight gallium and iron chelates in the circulation may also be taken up by certain cells through a shared Tf-independent pathway. In this pathway, gallium may enhance cellular iron uptake and vice versa. In cells, gallium can be detected in a low-molecular-weight pool. TfR1 and ferritin mRNA translation: Consistent with the induction of cellular iron deprivation, cells exposed to gallium display an increase in TfR1 mRNA and protein. This results from an increase in IRP-IRE mRNA interaction that leads to increased TfR mRNA translation. RR: Gallium blocks iron incorporation into the R2 subunit and may itself be incorporated into this subunit, rendering it inactive. Gallium also blocks RR enzyme activity more directly through competitive inhibition of substrate binding. This could result from the formation of Ga-ADP/CDP complexes that compete with (Fe)-ADP/CDP binding to the enzyme. The inhibition of RR activity contributes to gallium-induced cell death. Iron-dependent mitochondrial function: Gallium may perturb mitochondrial function by action on the numerous iron-containing proteins present in the citric acid cycle and the electron transport chain (shown in Fig. 4). Upstream from the mitochondrion (mito), gallium may activate proapoptotic Bax, which translocates to the mitochondria, produces a loss of mitochondrial membrane potential, and the release of cytochrome c and apoptogenic factors to the cytoplasm. This triggers the activation of effector caspases-3 and -7, leading to apoptotic cell death. ADP, adenosine diphosphate; CDP, cytidine diphosphate.