title: TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I assembly factor through association with the MCIA complex.
abstract: Complex I (CI) of the electron transport chain, a large membrane-embedded NADH dehydrogenase, couples electron transfer to the release of protons into the mitochondrial inner membrane space to promote ATP production through ATP synthase. In addition to being a central conduit for ATP production, CI activity has been linked to neurodegenerative disorders, including Parkinson's disease. CI is built in a stepwise fashion through the actions of several assembly factors. We employed interaction proteomics to interrogate the molecular associations of 15 core subunits and assembly factors previously linked to human CI deficiency, resulting in a network of 101 proteins and 335 interactions (edges). TIMMDC1, a predicted 4-pass membrane protein, reciprocally associated with multiple members of the MCIA CI assembly factor complex and core CI subunits and was localized in the mitochondrial inner membrane, and its depletion resulted in reduced CI activity and cellular respiration. Quantitative proteomics demonstrated a role for TIMMDC1 in assembly of membrane-embedded and soluble arms of the complex. This study defines a new membrane-embedded CI assembly factor and provides a resource for further analysis of CI biology.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Guarani
authors.forename: Joao
authors.initials: J
authors.lastname: Paulo
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Edward L
authors.initials: EL
authors.lastname: Huttlin
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008969:Molecular Sequence Data; D040901:Proteomics / Q000379:methods
chemical_list: D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C421265:TIMMDC1 protein, human; D042967:Electron Transport Complex I