Figure 2: Mechanisms of iron accumulation in the brain and links to carcinogenesis.

Multiple conditions contribute to iron accumulation in the brain including advanced age, various human diseases, dietary choices, cerebrovascular bleeding, inflammation, pathogens, and increased blood brain barrier (BBB) permeability. Iron is normally stored, alongside other metals, in endolysosomes. Deregulated iron release into the cytosol appears capable of contributing to various pathogenesis including carcinogenesis. X-ray and γ-radiation can induce endolysosome membrane permeability (LMP; left side of figure) leading to increased mitochondrial iron and downstream increases in reactive oxygen species (ROS), mitochondrial division (fission), and the accumulation of mtDNA mutations. Drug-induced de-acidification of endolysosomes (right side) can be caused by a wide range of carcinogenic drugs and compounds including tamoxifen, nicotine, ethyl alcohol, and chloroquine. Iron released into the cytosol can also lead to an accumulation of iron in the nucleus where it produces hydroxyl radicals that cause oxidative damage to DNA and strand breaks leading to genomic DNA mutations. The endocytosed iron chelator deferoxamine (DFO) can decrease the downstream and deleterious effects of iron released from endolysosomes.