## 3 Brief Overview of Iron Metabolism, the Labile Iron Pool and How It Is Altered in Cancer
### Cellular Iron Homeostasis
Hepcidin expression correlates with both cellular and serum iron levels. When iron levels are high, hepcidin is produced in the liver. This consequently results in the degradation of FPN-1 in duodenal enterocytes and hepatocytes, which prevents these cells from exporting iron [50]. In contrast, this process does not occur when iron levels are low, and the duodenal and hepatocytes can export iron [54]. Mitochondrial Iron Metabolism and Fe-S Biosynthesis  
Iron plays a critical role in the mitochondria; however, the exact mechanisms of how the mitochondria receive iron have not been fully elucidated. Mitochondrial iron is the leading destination for cytosolic labile iron. Thus, cytosolic iron from the labile iron pool must cross the outer mitochondrial membrane (OMM) before being utilised for Fe-S cluster synthesis within the mitochondria with its own labile iron pool. The mitochondrial labile iron pool is also susceptible to ROS as the mitochondria are a site of oxygen consumption. There are two hypotheses as to how mitochondrial iron crosses the OMM. The first is that STEAP3 reduces Fe\({}^{3+}\) iron in the endosome [55]. The second is the kiss and run theory, where there is the docking of the endosome containing transferrin-bound iron [56]. More evidence is needed to clarify the exact mechanism or mechanisms involved for iron to cross the OMM. However, the mechanisms for iron to travel from the OMM to the inner mitochondrial membrane (IMM) have been elucidated. It involves iron being brought across the IMM by mitoferrin 1 and mitoferrin 2. It has been shown that purified recombinant mitoferrin transports free iron and that its reduced expression results in iron depletion [57; 58]. Once transferred across the IMM by mitoferrin 1 and mitoferrin 2, it is incorporated into Fe-S clusters by frataxin and GLRX5 (Glutaredoxin-related protein 5) for many processes, including DNA repair enzymes [59]. The mitochondrial iron sulphur cluster (ISC) assembly machinery starts Fe-S biogenesis. This complex multistep process can be broken down into four main steps. It is crucial not only for the maturation of Fe-S clusters in the mitochondria but also for cytosolic and nuclear Fe-S cluster proteins [60]. The first [2 Fe-2S] cluster is synthesised de novo by several vital ISC proteins; this takes place on the ISU1 scaffold protein [61]. Next, an ATP-dependent chaperone protein aids the Fe/S cluster release from Isu1 and its transfer to monothiol glutaredoxin [62]. It can then be used in proteins that require a [2 Fe-2S] cluster or passed to the ISC for [4 Fe-4S] cluster synthesis; the latter is the third step. Lastly, the fourth step involves the insertion of the [4 Fe-4S] cluster into apoproteins that require it by ISC machinery [63]. The labile iron pool has crosstalk between the mitochondrial labile iron pool and the cytosolic, where the demand for Fe-S clusters and heme synthesis in the mitochondria can lower the cytosolic levels of labile iron. The labile iron in both the cytosol and mitochondria that iron chelators target theoretically makes less iron available for incorporation into crucial iron-requiring enzymes.