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Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants
The PTEN-induced kinase 1 (PINK1) is a mitochondrial kinase, and pink1 mutations cause early onset Parkinson's disease (PD) in humans. Loss of pink1 in Drosophila leads to defects in mitochondrial function, and genetic data suggest that another PD-related gene product, Parkin, acts with pink1 t...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636082/ https://www.ncbi.nlm.nih.gov/pubmed/23637640 http://dx.doi.org/10.1371/journal.pgen.1003478 |
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author | Esposito, Giovanni Vos, Melissa Vilain, Sven Swerts, Jef De Sousa Valadas, Jorge Van Meensel, Stefanie Schaap, Onno Verstreken, Patrik |
author_facet | Esposito, Giovanni Vos, Melissa Vilain, Sven Swerts, Jef De Sousa Valadas, Jorge Van Meensel, Stefanie Schaap, Onno Verstreken, Patrik |
author_sort | Esposito, Giovanni |
collection | PubMed |
description | The PTEN-induced kinase 1 (PINK1) is a mitochondrial kinase, and pink1 mutations cause early onset Parkinson's disease (PD) in humans. Loss of pink1 in Drosophila leads to defects in mitochondrial function, and genetic data suggest that another PD-related gene product, Parkin, acts with pink1 to regulate the clearance of dysfunctional mitochondria (mitophagy). Consequently, pink1 mutants show an accumulation of morphologically abnormal mitochondria, but it is unclear if other factors are involved in pink1 function in vivo and contribute to the mitochondrial morphological defects seen in specific cell types in pink1 mutants. To explore the molecular mechanisms of pink1 function, we performed a genetic modifier screen in Drosophila and identified aconitase (acon) as a dominant suppressor of pink1. Acon localizes to mitochondria and harbors a labile iron-sulfur [4Fe-4S] cluster that can scavenge superoxide to release hydrogen peroxide and iron that combine to produce hydroxyl radicals. Using Acon enzymatic mutants, and expression of mitoferritin that scavenges free iron, we show that [4Fe-4S] cluster inactivation, as a result of increased superoxide in pink1 mutants, results in oxidative stress and mitochondrial swelling. We show that [4Fe-4S] inactivation acts downstream of pink1 in a pathway that affects mitochondrial morphology, but acts independently of parkin. Thus our data indicate that superoxide-dependent [4Fe-4S] inactivation defines a potential pathogenic cascade that acts independent of mitophagy and links iron toxicity to mitochondrial failure in a PD–relevant model. |
format | Online Article Text |
id | pubmed-3636082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36360822013-05-01 Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants Esposito, Giovanni Vos, Melissa Vilain, Sven Swerts, Jef De Sousa Valadas, Jorge Van Meensel, Stefanie Schaap, Onno Verstreken, Patrik PLoS Genet Research Article The PTEN-induced kinase 1 (PINK1) is a mitochondrial kinase, and pink1 mutations cause early onset Parkinson's disease (PD) in humans. Loss of pink1 in Drosophila leads to defects in mitochondrial function, and genetic data suggest that another PD-related gene product, Parkin, acts with pink1 to regulate the clearance of dysfunctional mitochondria (mitophagy). Consequently, pink1 mutants show an accumulation of morphologically abnormal mitochondria, but it is unclear if other factors are involved in pink1 function in vivo and contribute to the mitochondrial morphological defects seen in specific cell types in pink1 mutants. To explore the molecular mechanisms of pink1 function, we performed a genetic modifier screen in Drosophila and identified aconitase (acon) as a dominant suppressor of pink1. Acon localizes to mitochondria and harbors a labile iron-sulfur [4Fe-4S] cluster that can scavenge superoxide to release hydrogen peroxide and iron that combine to produce hydroxyl radicals. Using Acon enzymatic mutants, and expression of mitoferritin that scavenges free iron, we show that [4Fe-4S] cluster inactivation, as a result of increased superoxide in pink1 mutants, results in oxidative stress and mitochondrial swelling. We show that [4Fe-4S] inactivation acts downstream of pink1 in a pathway that affects mitochondrial morphology, but acts independently of parkin. Thus our data indicate that superoxide-dependent [4Fe-4S] inactivation defines a potential pathogenic cascade that acts independent of mitophagy and links iron toxicity to mitochondrial failure in a PD–relevant model. Public Library of Science 2013-04-25 /pmc/articles/PMC3636082/ /pubmed/23637640 http://dx.doi.org/10.1371/journal.pgen.1003478 Text en © 2013 Esposito et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Esposito, Giovanni Vos, Melissa Vilain, Sven Swerts, Jef De Sousa Valadas, Jorge Van Meensel, Stefanie Schaap, Onno Verstreken, Patrik Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants |
title | Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants |
title_full | Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants |
title_fullStr | Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants |
title_full_unstemmed | Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants |
title_short | Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants |
title_sort | aconitase causes iron toxicity in drosophila pink1 mutants |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636082/ https://www.ncbi.nlm.nih.gov/pubmed/23637640 http://dx.doi.org/10.1371/journal.pgen.1003478 |
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