| http://purl.uniprot.org/citations/31533452 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/31533452 | http://www.w3.org/2000/01/rdf-schema#comment | "BackgroundThe mitochondrial calcium uniporter (mtCU) is an ≈700-kD multisubunit channel residing in the inner mitochondrial membrane required for mitochondrial Ca2+ (mCa2+) uptake. Here, we detail the contribution of MCUB, a paralog of the pore-forming subunit MCU, in mtCU regulation and function and for the first time investigate the relevance of MCUB to cardiac physiology.MethodsWe created a stable MCUB knockout cell line (MCUB-/-) using CRISPR-Cas9n technology and generated a cardiac-specific, tamoxifen-inducible MCUB mutant mouse (CAG-CAT-MCUB x MCM; MCUB-Tg) for in vivo assessment of cardiac physiology and response to ischemia/reperfusion injury. Live-cell imaging and high-resolution spectrofluorometery were used to determine intracellular Ca2+ exchange and size-exclusion chromatography; blue native page and immunoprecipitation studies were used to determine the molecular function and impact of MCUB on the high-molecular-weight mtCU complex.ResultsUsing genetic gain- and loss-of-function approaches, we show that MCUB expression displaces MCU from the functional mtCU complex and thereby decreases the association of mitochondrial calcium uptake 1 and 2 (MICU1/2) to alter channel gating. These molecular changes decrease MICU1/2-dependent cooperative activation of the mtCU, thereby decreasing mCa2+ uptake. Furthermore, we show that MCUB incorporation into the mtCU is a stress-responsive mechanism to limit mCa2+ overload during cardiac injury. Indeed, overexpression of MCUB is sufficient to decrease infarct size after ischemia/reperfusion injury. However, MCUB incorporation into the mtCU does come at a cost; acute decreases in mCa2+ uptake impair mitochondrial energetics and contractile function.ConclusionsWe detail a new regulatory mechanism to modulate mtCU function and mCa2+ uptake. Our results suggest that MCUB-dependent changes in mtCU stoichiometry are a prominent regulatory mechanism to modulate mCa2+ uptake and cellular physiology."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.org/dc/terms/identifier | "doi:10.1161/circulationaha.118.037968"xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Zhang X."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Elrod J.W."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Tomar D."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Lambert J.P."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Gao E."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Luongo T.S."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Jadiya P."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Shah N.S."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Lucchese A.M."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/author | "Kolmetzky D.W."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/date | "2019"xsd:gYear |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/name | "Circulation"xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/pages | "1720-1733"xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/title | "MCUB Regulates the Molecular Composition of the Mitochondrial Calcium Uniporter Channel to Limit Mitochondrial Calcium Overload During Stress."xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://purl.uniprot.org/core/volume | "140"xsd:string |
| http://purl.uniprot.org/citations/31533452 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/31533452 |
| http://purl.uniprot.org/citations/31533452 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/31533452 |
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| http://purl.uniprot.org/uniprot/#_D6RI54-mappedCitation-31533452 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31533452 |
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| http://purl.uniprot.org/uniprot/#_Q810S1-mappedCitation-31533452 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31533452 |