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 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.
Mastroberardino
Pier Giorgio
PG
Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA. mastroberardinopg@upmc.edu
Hoffman
Eric K
EK
Horowitz
Maxx P
MP
Betarbet
Ranjita
R
Taylor
Georgia
G
Cheng
Dongmei
D
Na
Hye Mee
HM
Gutekunst
Claire-Anne
CA
Gearing
Marla
M
Trojanowski
John Q
JQ
Anderson
Marjorie
M
Chu
Charleen T
CT
Peng
Junmin
J
Greenamyre
J Timothy
JT
D000368:Aged; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008928:Mitochondria / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000503:physiopathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D011990:Receptors, Transferrin / Q000378:metabolism*; D012402:Rotenone; D015398:Signal Transduction; D013378:Substantia Nigra / Q000503:physiopathology*; D014168:Transferrin / Q000378:metabolism*
D011990:Receptors, Transferrin; C503640:TFR2 protein, human; D014168:Transferrin; D012402:Rotenone; D007501:Iron; D042967:Electron Transport Complex I; D004298:Dopamine