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

Neurobiology of Disease

Maxx P. Horowitz¹  Marjorie Anderson²  Eric K. Hoffman²  Georgia Taylor²  J. Timothy Greenamyre³  Marla Gearing⁴  Charleen T. Chu⁵  Claire-Anne Gutekunst⁵  Hye Mee Na⁵  Pier Giorgio Mastroberardino⁶  Ranjita Betarbet⁶  John Q. Trojanowski⁶  Junmin Peng⁷  Dongmei Cheng⁸ 

[1] Corresponding author. Department of Neurology, University of Pittsburgh, 3501 fifth avenue, Pittsburgh, PA 15260, USA Fax: [phone].;Pittsburgh Institute for Neurodegenerative Diseases, USA;Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA 19104, USA;Department of Human Genetics, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USA;Department of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USA;Department of Neurology, University of Pittsburgh, 3501 fifth avenue, Pittsburgh, PA 15260, USA;Department of Pathology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USA;Medical Scientist Training Program and Center for Neuroscience, University of Pittsburgh, USA;

关键词: Parkinson's disease;    Rotenone;    Oxidative stress;    Mitochondria;    Iron;    Transferrin;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown