title: Reduced respiratory control with ADP and changed pattern of respiratory chain enzymes as a result of selective deficiency of the mitochondrial ATP synthase.
abstract: The F(o)F(1)-ATPase, a multisubunit protein complex of the inner mitochondrial membrane, produces most of the ATP in mammalian cells. Mitochondrial diseases as a result of a dysfunction of ATPase can be caused by mutations in mitochondrial DNA-encoded ATPase subunit a or rarely by an ATPase defect of nuclear origin. Here we present a detailed functional and immunochemical analysis of a new case of selective and generalized ATPase deficiency found in an Austrian patient. The defect manifested with developmental delay, muscle hypotonia, failure to thrive, ptosis, and varying lactic acidemia (up to 12 mmol/L) beginning from the neonatal period. A low-degree dilated cardiomyopathy of the left ventricle developed between the age of 1 and 2 y. A >90% decrease in oligomycin-sensitive ATPase activity and an 86% decrease in the content of the ATPase complex was found in muscle mitochondria. It was associated with a significant decrease of ADP-stimulated respiration of succinate (1.5-fold) and respiratory control with ADP (1.7-fold) in permeabilized muscle fibers, and with a slight decrease of the respiratory chain complex I and compensatory increase in the content of complexes III and IV. The same ATPase deficiency without an increase in respiratory chain complexes was found in fibroblasts, suggesting a generalized defect with tissue-specific manifestation. Absence of any mutations in mitochondrial ATP6 and ATP8 genes indicates a nuclear origin of the defect.
authors.affiliation: Department of Pediatrics, General Hospital Salzburg, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.forename: Jan
authors.initials: J
authors.lastname: Paul
authors.forename: Petr
authors.initials: P
authors.lastname: Pecina
authors.forename: Peter
authors.initials: P
authors.lastname: Kurnik
authors.forename: Holger
authors.initials: H
authors.lastname: Förster
authors.forename: Ulrike
authors.initials: U
authors.lastname: Fötschl
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.forename: Josef
authors.initials: J
authors.lastname: Houstek
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D002467:Cell Nucleus / Q000235:genetics; D002675:Child, Preschool; D004579:Electron Transport; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008931:Mitochondria, Muscle / Q000378:metabolism; D017240:Mitochondrial Myopathies / Q000201:enzymology / Q000235:genetics; D025261:Mitochondrial Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics*; D010085:Oxidative Phosphorylation
chemical_list: D000244:Adenosine Diphosphate; D025261:Mitochondrial Proton-Translocating ATPases