Parkinson’s Disease: The Mitochondria-Iron Link

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.