title: The Assembly Pathway of Mitochondrial Respiratory Chain Complex I.
abstract: Mitochondrial complex I is the largest integral membrane enzyme of the respiratory chain and consists of 44 different subunits encoded in the mitochondrial and nuclear genome. Its biosynthesis is a highly complicated and multifaceted process involving at least 14 additional assembly factors. How these subunits assemble into a functional complex I and where the assembly factors come into play is largely unknown. Here, we applied a dynamic complexome profiling approach to elucidate the assembly of human mitochondrial complex I and its further incorporation into respiratory chain supercomplexes. We delineate the stepwise incorporation of all but one subunit into a series of distinct assembly intermediates and their association with known and putative assembly factors, which had not been implicated in this process before. The resulting detailed and comprehensive model of complex I assembly is fully consistent with recent structural data and the remarkable modular architecture of this multiprotein complex.
authors.affiliation: Molecular Bioenergetics Group, Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert-Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands; Cluster of Excellence Frankfurt Macromolecular Complexes, Goethe-University, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Germany.
authors.forename: Sergio
authors.initials: S
authors.lastname: Guerrero-Castillo
authors.affiliation: OXPHOS Biogenesis Group, Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert-Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands; Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Baertling
authors.affiliation: Mitochondrial Neurobiochemistry Group, Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert-Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kownatzki
authors.affiliation: Proteomics Group, Radboud Center for Mitochondrial Medicine, Radboud Proteomics Center, Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Geert-Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Wessels
authors.affiliation: Mitochondrial Neurobiochemistry Group, Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert-Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Susanne
authors.initials: S
authors.lastname: Arnold
authors.affiliation: Molecular Bioenergetics Group, Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert-Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands; Cluster of Excellence Frankfurt Macromolecular Complexes, Goethe-University, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.affiliation: OXPHOS Biogenesis Group, Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud University Medical Center, Geert-Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands. Electronic address: leo.nijtmans@radboudumc.nl.
authors.forename: Leo
authors.initials: L
authors.lastname: Nijtmans
mesh_terms: D045744:Cell Line, Tumor; D002701:Chloramphenicol / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D020543:Proteome / Q000378:metabolism; D013997:Time Factors
chemical_list: D046912:Multiprotein Complexes; D021122:Protein Subunits; D020543:Proteome; D002701:Chloramphenicol; D042967:Electron Transport Complex I
keywords: assembly; assembly factors; complex I; complexome profiling; mitochondria; oxidative phosporylation