Parkinson’s Disease: The Mitochondria-Iron Link

Figure 1

(a) Mitochondrial iron traffic. Iron enters mitochondria from the cLIP in a process mediated by the inner mitochondrial iron transporter Mtfn2 and probably by DMT1 located in the outer membrane. Upon entering, iron incorporates into the mLIP from where it distributes for heme and ISC synthesis or for storage in mFt. Heme leaves the mitochondrion through ABCB10 and the mitochondrial heme exporter FLVCR1b, located in the inner and outer mitochondrial membranes, respectively. ISCs are transported out of the mitochondrion by the ABCB7 transporter and probably by the ABCB8 transporter as well. In the cytoplasm, ISCs bind to the corresponding apoproteins. IRP1 binds a 4Fe-4S cluster; the holoprotein is inactive to induce the transcriptional regulation of cell iron-import proteins like DMT1 and TfR1. In contrast, apo-IRP1, normally abundant under low cell iron conditions, upregulates the expression of iron-import proteins like DMT1 and TfR1. ABC: ATP-binding cassette transporter; cLIP: cytoplasmic labile iron pool; DMT1: divalent metal transporter 1; FLVCR1b: feline leukemia virus subgroup C receptor 1B transporter; ISC: iron-sulfur cluster; mFt: mitochondrial ferritin; mLIP: mitochondrial iron pool; Mtfn2: mitoferrin-2; TfR1: transferrin receptor 1. (b) Kinetic determination of iron entrance into the cLIP and mLIP. SH-SY5Y cells preloaded with the mitochondrial iron sensor rhodamine B-[(1,10-phenanthroline-5-yl)aminocarbonyl]benzyl ester (RPA) and the cytoplasmic iron sensor calcein were challenged with 40 μM ferrous ammonium sulfate (Fe) and changes in RPA and calcein fluorescence were followed in a multiplate fluorescence reader [61, 62]. Iron binding quenches RPA and calcein fluorescence; thus, a decrease in RPA or calcein fluorescence is directly proportional to iron entrance into the mLIP or cLIP, respectively. Note that the initial rate of iron entrance into the mLIP ( ) is larger than the rate of iron entrance into the cytoplasmic LIP ( ). Values represent mean ± SD of quadruplicates; .

(a)

(b)