Aconitase causes iron toxicity in Drosophila pink1 mutants

PLoS Genet. 2013 Apr;9(4):e1003478. doi: 10.1371/journal.pgen.1003478. Epub 2013 Apr 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitate Hydratase*
  • Animals
  • Drosophila Proteins / genetics
  • Drosophila* / genetics
  • Humans
  • Iron / metabolism
  • Mitochondria / genetics
  • Parkinson Disease / genetics

Substances

  • Drosophila Proteins
  • Iron
  • Aconitate Hydratase

Grant support

This work was supported by a Marie Curie Excellence Grant (MEXT-CT-2006-042267 http://cordis.europa.eu/mariecurie-actions/ext/home.html), the ERC Starting Grant (260678 http://erc.europa.eu/starting-grants), the Research Foundation Flanders (FWO grants G053913, G079013, G095511, and G074709 http://www.fwo.be/), the Methusalem grant of the Flemish Government (http://www.belgium.be/en/about_belgium/government/communities/flemish_community), the Francqui Foundation (http://www.francquifoundation.be/), the Hercules Foundation (AKUL/09/037 http://www.herculesstichting.be/in_English/index.php), the Instutuut voor Wetenschap en Technologie (IWT O&O http://www.iwt.be/), the Interuniversity Attraction Pole program by BELSPO (IAP P7/16 NEUROBRAINNET http://www.belspo.be/belspo/iap/index_en.stm), the research fund KU Leuven (OT Start, GOA/13/017, http://www.kuleuven.be/research/funding/bof/), and VIB (http://www.vib.be). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.