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

Biochimica Et Biophysica Acta. Molecular Basis of Disease
Pamela UrrutiaMarco T Núñez

Abstract

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...Continue Reading

Citations

Nov 30, 2018·Annual Review of Physiology·Diane M Ward, Suzanne M Cloonan
Oct 24, 2018·Pharmaceuticals·Marco T Nuñez, Pedro Chana-Cuevas
Feb 4, 2021·The International Journal of Neuroscience·Thomas M Berry, Ahmed A Moustafa
Jan 10, 2021·Antioxidants·Pamela J UrrutiaMarco Tulio Núñez
Jan 12, 2021·Prostaglandins, Leukotrienes, and Essential Fatty Acids·Frederic MármolAlbert Martínez-Pinteño

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