A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease
Open accessAbstract
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.
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Disruption of iron homoeostasis can interfere with mitochondrial functions and accelerate the progression of neurodegenerative mechanisms.
“Disruption of iron homoeostasis can interfere with mitochondrial functions and as a result accelerate the progression of neurodegenerative mechanisms.63,64”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [63]
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- Authors
- Mastroberardino, P. G., Hoffman, E. K., Horowitz, M. P., Betarbet, R., Taylor, G., Cheng, D., Na, H. M., Gutekunst, C.-A., Gearing, M., Trojanowski, J. Q., Anderson, M., Chu, C. T., Peng, J., & Greenamyre, J. T.
- Affiliations
- University of Pittsburgh (US)
- Emory University (US)
- University of Pennsylvania (US)
- University of Washington (US)
- Corresponding author
- Mastroberardino, Pier Giorgio
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 34
- Issue
- 3
- Pages
- 417-431
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC2784936
- OpenAlex
- W2001110041
- Cited by
- 195
- References
- 70
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 12 · 2023: 10 · 2022: 13 · 2021: 15 · 2020: 12 · 2019: 11 · 2018: 8 · 2017: 12 · 2016: 13 · 2015: 14 · 2014: 14 · 2013: 15 · 2012: 6
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- American Parkinson Disease Association
- Parkinson Vereniging
- National Institutes of Health
- National Institute on Aging (AG 05-133, P50AG005133)
- National Institute of Neurological Disorders and Stroke (P01NS059806)
- National Institute of Environmental Health Sciences (K99ES016352)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- Parkinson's disease, transferrin, transferrin receptor 2, mitochondrial iron transport, substantia nigra, dopaminergic neurons, mitochondrial targeting sequence, mitochondrial complex I, iron accumulation, rotenone, oxidative stress, ferrous iron, free radicals, therapeutic target
- MeSH terms
- Aged, Animals, Dopamine, Humans, Iron, Macaca fascicularis, Macaca mulatta, Mitochondria, Neurons, Oxidation-Reduction, Parkinson Disease, Parkinson Disease, Secondary, Rats, Inbred Lew, Receptors, Transferrin, Rotenone, Substantia Nigra, Transferrin, Signal Transduction, Electron Transport Complex I, Rats
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