title: MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation.
abstract: Mitochondrial respiratory-chain complexes assemble from subunits of dual genetic origin assisted by specialized assembly factors. Whereas core subunits are translated on mitochondrial ribosomes, others are imported after cytosolic translation. How imported subunits are ushered to assembly intermediates containing mitochondria-encoded subunits is unresolved. Here, we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation and reveal assembly factors promoting biogenesis of human respiratory-chain complexes. We find that TIM21, a subunit of the inner-membrane presequence translocase, is also present in the major assembly intermediates containing newly mitochondria-synthesized and imported respiratory-chain subunits, which we term MITRAC complexes. Human TIM21 is dispensable for protein import but required for integration of early-assembling, presequence-containing subunits into respiratory-chain intermediates. We establish an unexpected molecular link between the TIM23 transport machinery and assembly of respiratory-chain complexes that regulate mitochondrial protein synthesis in response to their assembly state.
authors.affiliation: Department for Biochemistry II, University of Göttingen, D-37073 Göttingen, Germany.
authors.forename: David U
authors.initials: DU
authors.lastname: Mick
authors.forename: Sven
authors.initials: S
authors.lastname: Dennerlein
authors.forename: Heike
authors.initials: H
authors.lastname: Wiese
authors.forename: Robert
authors.initials: R
authors.lastname: Reinhold
authors.forename: David
authors.initials: D
authors.lastname: Pacheu-Grau
authors.forename: Isotta
authors.initials: I
authors.lastname: Lorenzi
authors.forename: Florin
authors.initials: F
authors.lastname: Sasarman
authors.forename: Woranontee
authors.initials: W
authors.lastname: Weraarpachai
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
authors.forename: Bettina
authors.initials: B
authors.lastname: Warscheid
authors.forename: Peter
authors.initials: P
authors.lastname: Rehling
mesh_terms: D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D014176:Protein Biosynthesis
chemical_list: C578539:COA3 protein, human; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; C092928:Surf-1 protein; C578538:TIMM21 protein, human; C438387:TIMM23 protein, human; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D003576:Electron Transport Complex IV