Callegari, Sylvie

[["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","31"],["dc.bibliographiccitation.journal","Frontiers in Cell and Developmental Biology"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Callegari, Sylvie"],["dc.contributor.author","Dennerlein, Sven"],["dc.date.accessioned","2019-07-09T11:50:15Z"],["dc.date.available","2019-07-09T11:50:15Z"],["dc.date.issued","2018"],["dc.description.abstract","Mitochondria exist as compartmentalized units, surrounded by a selectively permeable double membrane. Within is contained the mitochondrial genome and protein synthesis machinery, required for the synthesis of OXPHOS components and ultimately, ATP production. Despite their physical barrier, mitochondria are tightly integrated into the cellular environment. A constant flow of information must be maintained to and from the mitochondria and the nucleus, to ensure mitochondria are amenable to cell metabolic requirements and also to feedback on their functional state. This review highlights the pathways by which mitochondrial stress is signaled to the nucleus, with a particular focus on the mitochondrial unfolded protein response (UPRmt) and the unfolded protein response activated by the mistargeting of proteins (UPRam). Although these pathways were originally discovered to alleviate proteotoxic stress from the accumulation of mitochondrial-targeted proteins that are misfolded or unimported, we review recent findings indicating that the UPRmt can also sense defects in mitochondrial translation. We further discuss the regulation of OXPHOS assembly and speculate on a possible role for mitochondrial stress pathways in sensing OXPHOS biogenesis."],["dc.identifier.doi","10.3389/fcell.2018.00031"],["dc.identifier.pmid","29644217"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15892"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59732"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/339580/EU//MITRAC"],["dc.relation.issn","2296-634X"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Sensing the Stress: A Role for the UPRmt and UPRam in the Quality Control of Mitochondria"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]