Cell death induced by mitochondrial complex I inhibition is mediated by Iron Regulatory Protein 1

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2017-09, Vol.1863 (9), p.2202-2209
• Main Authors: Urrutia, Pamela J., Aguirre, Pabla, Tapia, Victoria, Carrasco, Carlos M., Mena, Natalia P., Núñez, Marco T.
• Format: Article
• Language: English
• Subjects: Antigens, CD - genetics; Antigens, CD - metabolism; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell Death; Cell Line, Tumor; Electron Transport Complex I - antagonists & inhibitors; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Ferritin; Humans; Iron accumulation; Iron Regulatory Protein 1 - genetics; Iron Regulatory Protein 1 - metabolism; IRP1; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial dysfunction; Oxidative damage; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2017.05.015

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. [Display omitted] •Inhibition of mitochondrial complex I in SH-SY5Y neuroblastoma cells resulted in an iron accumulation phenotype together with increased oxidative modifications.•Knockdown of Iron Regulatory Protein 1 (IRP1) blocked this iron accumulation phenotype as well as the associated oxidative damage and the loss of cell viability.•IRP1 knockdown resulted in increased ferritin levels and a decreased labile iron pool.•It is proposed that IRP1 is a redox sensor that when deregulated by mitochondrial dysfunction mediates iron accumulation and cell death.