A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease

Abstract

More than 80 years after iron accumulation was initially described in the substantia nigra (SN) of Parkinson's disease (PD) patients, the mechanisms responsible for this phenomenon are still unknown. Similarly, how iron is delivered to its major recipients in the cell -mitochondria and the respiratory complexes -has yet to be elucidated. Here, we report a novel transferrin/transferrin receptor 2 (Tf/TfR2)-mediated iron transport pathway in mitochondria of SN dopamine neurons. We found that TfR2 has a previously uncharacterized mitochondrial targeting sequence that is sufficient to import the protein into these organelles. Importantly, the Tf/TfR2 pathway can deliver Tf bound iron to mitochondria and to the respiratory complex I as well. The pathway is redox-sensitive and oxidation of Tf thiols to disulfides induces release from Tf of highly reactive ferrous iron, which contributes to free radical production. In the rotenone model of PD, Tf accumulates in dopamine neurons, with much of it accumulating in the mitochondria. This is associated with iron deposition in SN, similar to what occurs in PD. In the human SN, TfR2 is also found in mitochondria of dopamine neurons, and in PD there is a dramatic increase of oxidized Tf in SN. Thus, we have discovered a novel mitochondrial iron transport system that goes awry in PD, and which may provide a new target for therapeutic intervention.

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

“…However, the presence of iron in PD brains is not simply an outcome of asynuclein aggregation, mitochondrial dysfunction, and DA cell death. An active process of iron import is suggested by the up-regulation of DMT1 ( + IRE), TfR1, and transferrin receptor 2 (TfR2) (278,298,380), and down-regulation of Fpn (6) in DA neurons of PD cases and mouse models of PD, while lossof-function mutations in DMT1 abolish this effect (380). Mutations in parkin increase DMT1 levels by inhibiting its degradation by the proteasomal pathway (374), providing the principal pathway of iron accumulation in DA neurons of the SN (380).…”

Single-Cell Redox Imaging Demonstrates a Distinctive Response of Dopaminergic Neurons to Oxidative Insults

“…Cells were fixed for 30 min in 4% paraformaldehyde, 1 mM N-ethylmaleimide, 2 lM Alexa680 maleimide, and 0.05% Triton X-100 prepared in phosphate-buffered saline (PBS) (pH 7.0). It is critical to control the pH of PBS to avoid nonspecific reactions (45). Cells were washed three times for 5 min in PBS to remove excess unreacted dye and then incubated for 30min in 5mM tris(2-carboxyethyl)phosphine (TCEP) in PBS.…”

“…Additionally, thiol oxidation has been involved in PD pathogenic events such as K-ATP-mediated neuronal depolarization (3,16,43) and transferring-mediated iron accumulation (45). Therefore, investigating the variations in thiol redox state and the associated signaling events will provide crucial information for understanding the healthy and diseased brain.…”

Iron chelation in the treatment of neurodegenerative diseases

“…Impairment or upregulation of any of these functions in brain cells may thus increase the need for iron. Increased myelin turnover in demyelinating disorders or compromised cellular energy metabolism in ischemic or mitochondrial disorders may enhance the cell iron uptake through the upregulation of transferrin receptors or activation of hypoxiainducible-factor-1␣ (HIF-1␣) [14,15]. It can be assumed that under normal circumstances cerebral iron can be recycled through lysosomal degradation of iron-rich proteins and organelles.…”