Cell death induced by mitochondrial complex I inhibition is mediated by Iron Regulatory Protein 1.

Mitochondrial dysfunction and oxidative damage, often accompanied by elevated intracellular iron levels, are pathophysiological features in a number of neurodegenerative processes. The question arises as to whether iron dyshomeostasis is a consequence of mitochondrial dysfunction. Here we have evaluated the role of Iron Regulatory Protein 1 (IRP1) in the death of SH-SY5Y dopaminergic neuroblastoma cells subjected to mitochondria complex I inhibition. We found that complex I inhibition was associated with increased levels of transferrin receptor 1 (TfR1) and iron uptake transporter divalent metal transporter 1 (DMT1), and decreased levels of iron efflux transporter Ferroportin 1 (FPN1), together with increased 55Fe uptake activity and an increased cytoplasmic labile iron pool. Complex I inhibition also resulted in increased oxidative modifications and increased cysteine oxidation that were inhibited by the iron chelators desferoxamine, M30 and Q1. Silencing of IRP1 abolished the rotenone-induced increase in 55Fe uptake activity and it protected cells from death induced by complex I inhibition. IRP1 knockdown cells presented higher ferritin levels, a lower iron labile pool, increased resistance to cysteine oxidation and decreased oxidative modifications. These results support the concept that IRP1 is an oxidative stress biosensor that mediates iron accumulation and cell death when deregulated by mitochondrial dysfunction. IRP1 activation, secondary to mitochondrial dysfunction, may underlie the events leading to iron dyshomeostasis and neuronal death observed in neurodegenerative disorders with an iron accumulation component.

Parkinson's Disease: The Mitochondria-Iron Link.

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.

Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons.

Neuronal death in Parkinson's disease (PD) is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2'-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH)-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death.

Shh Signaling through the Primary Cilium Modulates Rat Oligodendrocyte Differentiation.

Primary Cilia (PC) are a very likely place for signal integration where multiple signaling pathways converge. Two major signaling pathways clearly shown to signal through the PC, Sonic Hedgehog (Shh) and PDGF-Rα, are particularly important for the proliferation and differentiation of oligodendrocytes, suggesting that their interaction occurs in or around this organelle. We identified PC in rat oligodendrocyte precursor cells (OPCs) and found that, while easily detectable in early OPCs, PC are lost as these cells progress to terminal differentiation. We confirmed the interaction between these pathways, as cyclopamine inhibition of Hedgehog function impairs both PDGF-mediated OPC proliferation and Shh-dependent cell branching. However, we failed to detect PDGF-Rα localization into the PC. Remarkably, ciliobrevin-mediated disruption of PC and reduction of OPC process extension was counteracted by recombinant Shh treatment, while PDGF had no effect. Therefore, while PDGF-Rα-dependent OPC proliferation and survival most probably does not initiate at the PC, still the integrity of this organelle and cilium-centered pathway is necessary for OPC survival and differentiation.

Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders.

Synthesis of the iron-containing prosthetic groups-heme and iron-sulfur clusters-occurs in mitochondria. The mitochondrion is also an important producer of reactive oxygen species (ROS), which are derived from electrons leaking from the electron transport chain. The coexistence of both ROS and iron in the secluded space of the mitochondrion makes this organelle particularly prone to oxidative damage. Here, we review the elements that configure mitochondrial iron homeostasis and discuss the principles of iron-mediated ROS generation in mitochondria. We also review the evidence for mitochondrial dysfunction and iron accumulation in Alzheimer's disease, Huntington Disease, Friedreich's ataxia, and in particular Parkinson's disease. We postulate that a positive feedback loop of mitochondrial dysfunction, iron accumulation, and ROS production accounts for the process of cell death in various neurodegenerative diseases in which these features are present.