A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease
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 res...
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doaj-ae4df57a66d849599c7f41096719b5982021-03-20T04:57:15ZengElsevierNeurobiology of Disease1095-953X2009-06-01343417431A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's diseasePier Giorgio Mastroberardino0Eric K. Hoffman1Maxx P. Horowitz2Ranjita Betarbet3Georgia Taylor4Dongmei Cheng5Hye Mee Na6Claire-Anne Gutekunst7Marla Gearing8John Q. Trojanowski9Marjorie Anderson10Charleen T. Chu11Junmin Peng12J. Timothy Greenamyre13Department of Neurology, University of Pittsburgh, 3501 fifth avenue, Pittsburgh, PA 15260, USA; Pittsburgh Institute for Neurodegenerative Diseases, USA; Corresponding author. Department of Neurology, University of Pittsburgh, 3501 fifth avenue, Pittsburgh, PA 15260, USA Fax: +1 412 648 9766.Department of Neurology, University of Pittsburgh, 3501 fifth avenue, Pittsburgh, PA 15260, USA; Pittsburgh Institute for Neurodegenerative Diseases, USAMedical Scientist Training Program and Center for Neuroscience, University of Pittsburgh, USADepartment of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USADepartment of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USADepartment of Human Genetics, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USADepartment of Neurology, University of Pittsburgh, 3501 fifth avenue, Pittsburgh, PA 15260, USA; Pittsburgh Institute for Neurodegenerative Diseases, USADepartment of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USADepartment of Pathology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USACenter for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA 19104, USAUniversity of Washington, Department of Rehabilitation Medicine, Seattle, WA 98195, USAPittsburgh Institute for Neurodegenerative Diseases, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Human Genetics, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USADepartment of Neurology, University of Pittsburgh, 3501 fifth avenue, Pittsburgh, PA 15260, USA; Pittsburgh Institute for Neurodegenerative Diseases, USAMore 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.http://www.sciencedirect.com/science/article/pii/S0969996109000357Parkinson's diseaseRotenoneOxidative stressMitochondriaIronTransferrin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Pier Giorgio Mastroberardino Eric K. Hoffman Maxx P. Horowitz Ranjita Betarbet Georgia Taylor Dongmei Cheng Hye Mee Na Claire-Anne Gutekunst Marla Gearing John Q. Trojanowski Marjorie Anderson Charleen T. Chu Junmin Peng J. Timothy Greenamyre |
spellingShingle |
Pier Giorgio Mastroberardino Eric K. Hoffman Maxx P. Horowitz Ranjita Betarbet Georgia Taylor Dongmei Cheng Hye Mee Na Claire-Anne Gutekunst Marla Gearing John Q. Trojanowski Marjorie Anderson Charleen T. Chu Junmin Peng J. Timothy Greenamyre A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease Neurobiology of Disease Parkinson's disease Rotenone Oxidative stress Mitochondria Iron Transferrin |
author_facet |
Pier Giorgio Mastroberardino Eric K. Hoffman Maxx P. Horowitz Ranjita Betarbet Georgia Taylor Dongmei Cheng Hye Mee Na Claire-Anne Gutekunst Marla Gearing John Q. Trojanowski Marjorie Anderson Charleen T. Chu Junmin Peng J. Timothy Greenamyre |
author_sort |
Pier Giorgio Mastroberardino |
title |
A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease |
title_short |
A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease |
title_full |
A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease |
title_fullStr |
A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease |
title_full_unstemmed |
A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease |
title_sort |
novel transferrin/tfr2-mediated mitochondrial iron transport system is disrupted in parkinson's disease |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2009-06-01 |
description |
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. |
topic |
Parkinson's disease Rotenone Oxidative stress Mitochondria Iron Transferrin |
url |
http://www.sciencedirect.com/science/article/pii/S0969996109000357 |
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