Pacheu-Grau, David

[["dc.bibliographiccitation.firstpage","4135"],["dc.bibliographiccitation.issue","23"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.bibliographiccitation.lastpage","4144"],["dc.bibliographiccitation.volume","27"],["dc.contributor.author","Pacheu-Grau, David"],["dc.contributor.author","Callegari, Sylvie"],["dc.contributor.author","Emperador, Sonia"],["dc.contributor.author","Thompson, Kyle"],["dc.contributor.author","Aich, Abhishek"],["dc.contributor.author","Topol, Sarah E."],["dc.contributor.author","Spencer, Emily G."],["dc.contributor.author","McFarland, Robert"],["dc.contributor.author","Ruiz-Pesini, Eduardo"],["dc.contributor.author","Torkamani, Ali"],["dc.contributor.author","Taylor, Robert W."],["dc.contributor.author","Montoya, Julio"],["dc.contributor.author","Rehling, Peter"],["dc.date.accessioned","2019-07-09T11:50:15Z"],["dc.date.available","2019-07-09T11:50:15Z"],["dc.date.issued","2018"],["dc.description.abstract","Protein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans-mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole-exome sequencing identified compound heterozygous variants in the TIM22 gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts of TIM22 were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore-forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange."],["dc.identifier.doi","10.1093/hmg/ddy305"],["dc.identifier.pmid","30452684"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15894"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59733"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/51"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","SFB 1190 | P13: Protein Transport über den mitochondrialen Carrier Transportweg"],["dc.relation.issn","1460-2083"],["dc.relation.workinggroup","RG Rehling (Mitochondrial Protein Biogenesis)"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Mutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e32572"],["dc.bibliographiccitation.journal","eLife"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Aich, Abhishek"],["dc.contributor.author","Wang, Cong"],["dc.contributor.author","Chowdhury, Arpita"],["dc.contributor.author","Ronsör, Christin"],["dc.contributor.author","Pacheu-Grau, David"],["dc.contributor.author","Richter-Dennerlein, Ricarda"],["dc.contributor.author","Dennerlein, Sven"],["dc.contributor.author","Rehling, Peter"],["dc.date.accessioned","2018-05-03T09:03:52Z"],["dc.date.accessioned","2021-10-27T13:21:07Z"],["dc.date.available","2018-05-03T09:03:52Z"],["dc.date.available","2021-10-27T13:21:07Z"],["dc.date.issued","2018"],["dc.description.abstract","Cytochrome c oxidase of the mitochondrial oxidative phosphorylation system reduces molecular oxygen with redox equivalent-derived electrons. The conserved mitochondrial-encoded COX1- and COX2-subunits are the heme- and copper-center containing core subunits that catalyze water formation. COX1 and COX2 initially follow independent biogenesis pathways creating assembly modules with subunit-specific, chaperone-like assembly factors that assist in redox centers formation. Here, we find that COX16, a protein required for cytochrome c oxidase assembly, interacts specifically with newly synthesized COX2 and its copper center-forming metallochaperones SCO1, SCO2, and COA6. The recruitment of SCO1 to the COX2-module is COX16- dependent and patient-mimicking mutations in SCO1 affect interaction with COX16. These findings implicate COX16 in CuA-site formation. Surprisingly, COX16 is also found in COX1-containing assembly intermediates and COX2 recruitment to COX1. We conclude that COX16 participates in merging the COX1 and COX2 assembly lines."],["dc.identifier.doi","10.7554/eLife.32572"],["dc.identifier.gro","3142446"],["dc.identifier.pmid","29381136"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15212"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/91995"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/200"],["dc.language.iso","en"],["dc.notes.intern","Migrated from goescholar"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A06: Molekulare Grundlagen mitochondrialer Kardiomyopathien"],["dc.relation.issn","2050-084X"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.relation.workinggroup","RG Rehling (Mitochondrial Protein Biogenesis)"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","COX16 promotes COX2 metallation and assembly during respiratory complex IV biogenesis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]