title: The C8ORF38 homologue Sicily is a cytosolic chaperone for a mitochondrial complex I subunit.
abstract: Mitochondrial complex I (CI) is an essential component in energy production through oxidative phosphorylation. Most CI subunits are encoded by nuclear genes, translated in the cytoplasm, and imported into mitochondria. Upon entry, they are embedded into the mitochondrial inner membrane. How these membrane-associated proteins cope with the hydrophilic cytoplasmic environment before import is unknown. In a forward genetic screen to identify genes that cause neurodegeneration, we identified sicily, the Drosophila melanogaster homologue of human C8ORF38, the loss of which causes Leigh syndrome. We show that in the cytoplasm, Sicily preprotein interacts with cytosolic Hsp90 to chaperone the CI subunit, ND42, before mitochondrial import. Loss of Sicily leads to loss of CI proteins and preproteins in both mitochondria and cytoplasm, respectively, and causes a CI deficiency and neurodegeneration. Our data indicate that cytosolic chaperones are required for the subcellular transport of ND42.
authors.affiliation: Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Li
authors.forename: Manish
authors.initials: M
authors.lastname: Jaiswal
authors.forename: Vafa
authors.initials: V
authors.lastname: Bayat
authors.forename: Bo
authors.initials: B
authors.lastname: Xiong
authors.forename: Hector
authors.initials: H
authors.lastname: Sandoval
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.forename: Gabriela
authors.initials: G
authors.lastname: David
authors.forename: Claire
authors.initials: C
authors.lastname: Haueter
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007888:Leigh Disease / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology
chemical_list: D029721:Drosophila Proteins; D018841:HSP90 Heat-Shock Proteins; D024101:Mitochondrial Proteins; C530233:NDUFAF6 protein, human; D042967:Electron Transport Complex I