Cell death induced by mitochondrial complex I inhibition is mediated by Iron Regulatory Protein
Author
dc.contributor.author
Urrutia, Pamela J.
Author
dc.contributor.author
Aguirre, Pabla
Author
dc.contributor.author
Tapia, Victoria
Author
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Carrasco, Carlos M.
Author
dc.contributor.author
Mena, Natalia P.
Author
dc.contributor.author
Núñez González, Marco
Admission date
dc.date.accessioned
2018-06-21T22:07:38Z
Available date
dc.date.available
2018-06-21T22:07:38Z
Publication date
dc.date.issued
2017
Cita de ítem
dc.identifier.citation
BBA - Molecular Basis of Disease 1863 (2017) 2202–2209
es_ES
Identifier
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http://dx.doi.org/10.1016/j.bbadis.2017.05.015
Identifier
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https://repositorio.uchile.cl/handle/2250/149145
Abstract
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Mitochondrial dysfunction and oxidative damage, often accompanied by elevated intracellular iron levels, are
pathophysiological features in a number of neurodegenerative processes. The question arises as to whether iron
dyshomeostasis is a consequence of mitochondrial dysfunction. Here we have evaluated the role of Iron
Regulatory Protein 1 (IRP1) in the death of SH-SY5Y dopaminergic neuroblastoma cells subjected to mitochondria
complex I inhibition. We found that complex I inhibition was associated with increased levels of
transferrin receptor 1 (TfR1) and iron uptake transporter divalent metal transporter 1 (DMT1), and decreased
levels of iron efflux transporter Ferroportin 1 (FPN1), together with increased 55Fe uptake activity and an increased
cytoplasmic labile iron pool. Complex I inhibition also resulted in increased oxidative modifications and
increased cysteine oxidation that were inhibited by the iron chelators desferoxamine, M30 and Q1. Silencing of
IRP1 abolished the rotenone-induced increase in 55Fe uptake activity and it protected cells from death induced
by complex I inhibition. IRP1 knockdown cells presented higher ferritin levels, a lower iron labile pool, increased
resistance to cysteine oxidation and decreased oxidative modifications. These results support the concept that
IRP1 is an oxidative stress biosensor that mediates iron accumulation and cell death when deregulated by mitochondrial
dysfunction. IRP1 activation, secondary to mitochondrial dysfunction, may underlie the events
leading to iron dyshomeostasis and neuronal death observed in neurodegenerative disorders with an iron accumulation
component.
es_ES
Patrocinador
dc.description.sponsorship
Fondo Nacional de Ciencia y
Tecnología (FONDECYT) number 1130068