Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2011-1-28
pubmed:abstractText
Mitochondrial dysfunction is an important cause for neonatal liver disease. Disruption of genes encoding oxidative phosphorylation (OXPHOS) components usually causes embryonic lethality, and thus few disease models are available. We developed a mouse model for GRACILE syndrome, a neonatal mitochondrial disease with liver and kidney involvement, caused by a homozygous BCS1L mutation (232A>G). This gene encodes a chaperone required for incorporation of Rieske iron-sulfur protein (RISP) into complex III of respiratory chain. Homozygous mutant mice after 3 weeks of age developed striking similarities to the human disease: growth failure, hepatic glycogen depletion, steatosis, fibrosis, and cirrhosis, as well as tubulopathy, complex III deficiency, lactacidosis, and short lifespan. BCS1L was decreased in whole liver cells and isolated mitochondria of mutants at all ages. RISP incorporation into complex III was diminished in symptomatic animals; however, in young animals complex III was correctly assembled. Complex III activity in liver, heart, and kidney of symptomatic mutants was decreased to 20%, 40%, and 40% of controls, respectively, as demonstrated with electron flux kinetics through complex III. In high-resolution respirometry, CIII dysfunction resulted in decreased electron transport capacity through the respiratory chain under maximum substrate input. Complex I function, suggested to be dependent on a functional complex III, was, however, unaffected. CONCLUSION: We present the first viable model of complex III deficiency mimicking a human mitochondrial disorder. Incorporation of RISP into complex III in young homozygotes suggests another complex III assembly factor during early ontogenesis. The development of symptoms from about 3 weeks of age provides a convenient time window for studying the pathophysiology and treatment of mitochondrial hepatopathy and OXPHOS dysfunction in general.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1527-3350
pubmed:author
pubmed:copyrightInfo
Copyright © 2010 American Association for the Study of Liver Diseases.
pubmed:issnType
Electronic
pubmed:volume
53
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
437-47
pubmed:meshHeading
pubmed-meshheading:21274865-Acidosis, Lactic, pubmed-meshheading:21274865-Animals, pubmed-meshheading:21274865-Cholestasis, pubmed-meshheading:21274865-Disease Models, Animal, pubmed-meshheading:21274865-Electron Transport Complex III, pubmed-meshheading:21274865-Fetal Growth Retardation, pubmed-meshheading:21274865-Hemosiderosis, pubmed-meshheading:21274865-Homozygote, pubmed-meshheading:21274865-Liver Diseases, pubmed-meshheading:21274865-Metabolism, Inborn Errors, pubmed-meshheading:21274865-Mice, pubmed-meshheading:21274865-Mice, Mutant Strains, pubmed-meshheading:21274865-Mitochondrial Diseases, pubmed-meshheading:21274865-Molecular Chaperones, pubmed-meshheading:21274865-Mutation, pubmed-meshheading:21274865-Oxidative Phosphorylation, pubmed-meshheading:21274865-Renal Aminoacidurias
pubmed:year
2011
pubmed:articleTitle
The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: a viable mouse model for mitochondrial hepatopathy.
pubmed:affiliation
Department of Pediatrics, Clinical Sciences, Lund University, Lund, Sweden.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't