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Parkinson's Disease: The Mitochondria-Iron Link - PubMed

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Parkinson's Disease: The Mitochondria-Iron Link

Yorka Muñoz et al. Parkinsons Dis. 2016.

Abstract

Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson's disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1), a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences-mitochondrial dysfunction, iron accumulation, and oxidative damage-generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson's disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation-by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways-is a viable therapy for retarding this cycle.

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Figures

Figure 1
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 (K = 0.0536 ± 0.0021Δ(F/F 0)/sec) is larger than the rate of iron entrance into the cytoplasmic LIP (K = 0.0206 ± 0.0070Δ(F/F 0)/sec). Values represent mean ± SD of quadruplicates; P = 0.004.

Figure 2
Figure 2

The iron Chelator M30 protect SH-SY5Y cells from rotenone-induce lipid peroxidation. (a) Mitochondrial lipid peroxidation was evaluated by green/red fluorescence changes of C11-BODIPY581/591 (ThermoFisher Scientific-Molecular Probes) as described [63]. Oxidation of C11-BODIPY581/591 results in a shift of the fluorescence emission peak from 590 nm (red, nonoxidized) to 510 nm (green, oxidized). SH-SY5Y cells were preincubated or not for 24 hours with 500 nM of M30 in DMEM-10% FCS medium and then loaded for 15 minutes at 37°C with 1 μM C11-BODIPY581/591. Confocal images were obtained 15 minutes both before (Control, M30) and after (Rotenone, M30/Rotenone) applying 80 μM rotenone to the cells. Representative images are shown, where the ratio of green over (green + red) fluorescence was converted into a pseudothermal scale using the ImageJ program. (b) Changes in C11-BODIPY581/591 oxidation quantified by the thermal scale. Values represent the mean ± SD of 40–52 individual cell measures per experimental condition. Significance between mean differences was determined by one-way ANOVA and Tukey post hoc test. ∗∗∗ P < 0.001.

Figure 3
Figure 3

Mitochondrial dysfunction leads to iron accumulation and cell death. Mitochondrial dysfunction in PD, caused either by environmental or endogenous toxins or by genetic dysfunctions, results in decreased ATP and ISC synthesis. The lack of ISCs results in a false low iron signal and the spurious activation of IRP1. Activation of IRP1 results in increased redox-active iron levels mediated by increased expression of DMT1 and TfR1 and decreased expression of FPN1. Because of hydroxyl radical generation through the Fenton reaction, increased redox-active iron results in a decreased GSH/GSSG ratio and an increased oxidative load. The decrease in GSH further affects mitochondrial activity. With time, the increased oxidative load induces protein aggregation and saturation of the ubiquitin-proteasome system, further mitochondrial dysfunction, an inflammatory microenvironment, increased cytochrome c leak, and activation of death pathways. Iron chelation has been demonstrated to slow this cycle by decreasing iron-associated oxidative damage and by induction of cell survival and cell-rescue pathways. Environmental and endogenous toxins: paraquat, rotenone, MPTP, nitric oxide, 4-hydroxynonenal, advanced glycation end products, and aminochrome. Mitochondria-associated PD genes with mitochondrial dysfunction component: α-Syn, Parkin, PINK1, DJ-1, LRRK2, and ATP13A2.

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References

    1. Henchcliffe C., Beal F. M. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nature Clinical Practice Neurology. 2008;4(11):600–609. doi: 10.1038/ncpneuro0924. - DOI - PubMed
    1. Jenner P., Dexter D. T., Sian J., Schapira A. H. V., Marsden C. D. Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental Lewy body disease. Annals of Neurology. 1992;32(supplement 1):S82–S87. doi: 10.1002/ana.410320714. - DOI - PubMed
    1. Mullin S., Schapira A. H. V. Pathogenic mechanisms of neurodegeneration in parkinson disease. Neurologic Clinics. 2015;33(1):1–17. doi: 10.1016/j.ncl.2014.09.010. - DOI - PubMed
    1. Schapira A. H. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. The Lancet Neurology. 2008;7(1):97–109. doi: 10.1016/S1474-4422(07)70327-7. - DOI - PubMed
    1. Alam Z. I., Jenner A., Daniel S. E., et al. Oxidative DNA damage in the Parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. Journal of Neurochemistry. 1997;69(3):1196–1203. - PubMed

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