title: Genome-Wide Localization Study of Yeast Pex11 Identifies Peroxisome-Mitochondria Interactions through the ERMES Complex.
abstract: Pex11 is a peroxin that regulates the number of peroxisomes in eukaryotic cells. Recently, it was found that a mutation in one of the three mammalian paralogs, PEX11β, results in a neurological disorder. The molecular function of Pex11, however, is not known. Saccharomyces cerevisiae Pex11 has been shown to recruit to peroxisomes the mitochondrial fission machinery, thus enabling proliferation of peroxisomes. This process is essential for efficient fatty acid β-oxidation. In this study, we used high-content microscopy on a genome-wide scale to determine the subcellular localization pattern of yeast Pex11 in all non-essential gene deletion mutants, as well as in temperature-sensitive essential gene mutants. Pex11 localization and morphology of peroxisomes was profoundly affected by mutations in 104 different genes that were functionally classified. A group of genes encompassing MDM10, MDM12 and MDM34 that encode the mitochondrial and cytosolic components of the ERMES complex was analyzed in greater detail. Deletion of these genes caused a specifically altered Pex11 localization pattern, whereas deletion of MMM1, the gene encoding the fourth, endoplasmic-reticulum-associated component of the complex, did not result in an altered Pex11 localization or peroxisome morphology phenotype. Moreover, we found that Pex11 and Mdm34 physically interact and that Pex11 plays a role in establishing the contact sites between peroxisomes and mitochondria through the ERMES complex. Based on these results, we propose that the mitochondrial/cytosolic components of the ERMES complex establish a direct interaction between mitochondria and peroxisomes through Pex11.
authors.affiliation: Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
authors.forename: M
authors.initials: M
authors.lastname: Mattiazzi Ušaj
authors.affiliation: Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
authors.forename: M
authors.initials: M
authors.lastname: Brložnik
authors.affiliation: Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
authors.forename: P
authors.initials: P
authors.lastname: Kaferle
authors.affiliation: Faculty of Computer and Information Science, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia.
authors.forename: M
authors.initials: M
authors.lastname: Žitnik
authors.affiliation: Institute of Molecular Biosciences, University of Graz, BioTechMed Graz, Humboldtstrasse 50, A-8010 Graz, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Wolinski
authors.affiliation: Institute of Molecular Biosciences, University of Graz, BioTechMed Graz, Humboldtstrasse 50, A-8010 Graz, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Leitner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, BioTechMed Graz, Humboldtstrasse 50, A-8010 Graz, Austria.
authors.forename: S D
authors.initials: SD
authors.lastname: Kohlwein
authors.affiliation: Faculty of Computer and Information Science, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia; Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zupan
authors.affiliation: Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia. Electronic address: uros.petrovic@ijs.si.
authors.forename: U
authors.initials: U
authors.lastname: Petrovič
mesh_terms: D003600:Cytosol / Q000378:metabolism; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D016681:Genome, Fungal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D000074401:Peroxins; D020675:Peroxisomes / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C089419:MDM10 protein, S cerevisiae; C089418:MMM1 protein, S cerevisiae; C543343:Mdm12 protein, S cerevisiae; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; C092128:PEX11 protein, S cerevisiae; D000074401:Peroxins; D029701:Saccharomyces cerevisiae Proteins; C543344:mdm34 protein, S cerevisiae; D049452:Green Fluorescent Proteins
keywords: computational image analysis; high-content microscopy; lipid metabolism; organelle juxtaposition; peroxisomal disorders