title: Impaired ATP synthase assembly associated with a mutation in the human ATP synthase subunit 6 gene.
abstract: Mutations in human mitochondrial DNA are a well recognized cause of disease. A mutation at nucleotide position 8993 of human mitochondrial DNA, located within the gene for ATP synthase subunit 6, is associated with the neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome. To enable analysis of this mutation in control nuclear backgrounds, two different cell lines were transformed with mitochondria carrying NARP mutant mitochondrial DNA. Transformant cell lines had decreased ATP synthesis capacity, and many also had abnormally high levels of two ATP synthase sub-complexes, one of which was F(1)-ATPase. A combination of metabolic labeling and immunoblotting experiments indicated that assembly of ATP synthase was slowed and that the assembled holoenzyme was unstable in cells carrying NARP mutant mitochondrial DNA compared with control cells. These findings indicate that altered assembly and stability of ATP synthase are underlying molecular defects associated with the NARP mutation in subunit 6 of ATP synthase, yet intrinsic enzyme activity is also compromised.
authors.affiliation: Department of Molecular Pathology, University of Dundee, Ninewells Medical School, Dundee DD1 9SY, United Kingdom.
authors.forename: L G
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: N S
authors.initials: NS
authors.lastname: Henderson
authors.forename: G
authors.initials: G
authors.lastname: Attardi
authors.forename: I J
authors.initials: IJ
authors.lastname: Holt
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D001259:Ataxia / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D008715:Methionine / Q000378:metabolism; D018908:Muscle Weakness / Q000235:genetics; D009154:Mutation; D021122:Protein Subunits; D006180:Proton-Translocating ATPases / Q000737:chemistry / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D021122:Protein Subunits; D000255:Adenosine Triphosphate; D008715:Methionine; D006180:Proton-Translocating ATPases