Artículo de revista
Cell death induced by mitochondrial complex I inhibition is mediated by Iron Regulatory Protein
Fecha
2017Registro en:
BBA - Molecular Basis of Disease 1863 (2017) 2202–2209
Autor
Urrutia, Pamela J.
Aguirre, Pabla
Tapia, Victoria
Carrasco, Carlos M.
Mena, Natalia P.
Núñez González, Marco
Institución
Resumen
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.