title: Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit.
abstract: F1Fo-ATP synthase is a key enzyme of mitochondrial energy provision producing most of cellular ATP. So far, mitochondrial diseases caused by isolated disorders of the ATP synthase have been shown to result from mutations in mtDNA genes for the subunits ATP6 and ATP8 or in nuclear genes encoding the biogenesis factors TMEM70 and ATPAF2. Here, we describe a patient with a homozygous p.Tyr12Cys mutation in the epsilon subunit encoded by the nuclear gene ATP5E. The 22-year-old woman presented with neonatal onset, lactic acidosis, 3-methylglutaconic aciduria, mild mental retardation and developed peripheral neuropathy. Patient fibroblasts showed 60-70% decrease in both oligomycin-sensitive ATPase activity and mitochondrial ATP synthesis. The mitochondrial content of the ATP synthase complex was equally reduced, but its size was normal and it contained the mutated epsilon subunit. A similar reduction was found in all investigated F1 and Fo subunits with the exception of Fo subunit c, which was found to accumulate in a detergent-insoluble form. This is the first case of a mitochondrial disease due to a mutation in a nuclear encoded structural subunit of the ATP synthase. Our results indicate an essential role of the epsilon subunit in the biosynthesis and assembly of the F1 part of the ATP synthase. Furthermore, the epsilon subunit seems to be involved in the incorporation of subunit c to the rotor structure of the mammalian enzyme.
authors.affiliation: Department of Pediatrics, Paracelsus Medical University, Salzburg A5020, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.forename: Vendula
authors.initials: V
authors.lastname: Havlícková
authors.forename: Franz
authors.initials: F
authors.lastname: Zimmermann
authors.forename: Iris
authors.initials: I
authors.lastname: Magler
authors.forename: Vilma
authors.initials: V
authors.lastname: Kaplanová
authors.forename: Pavel
authors.initials: P
authors.lastname: Jesina
authors.forename: Alena
authors.initials: A
authors.lastname: Pecinová
authors.forename: Hana
authors.initials: H
authors.lastname: Nusková
authors.forename: Johannes
authors.initials: J
authors.lastname: Koch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.forename: Josef
authors.initials: J
authors.lastname: Houstek
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000201:enzymology; D006801:Humans; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000235:genetics; D025261:Mitochondrial Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D055815:Young Adult; D000097795:ATPase Inhibitory Protein
chemical_list: D025261:Mitochondrial Proton-Translocating ATPases; D011506:Proteins; D000097795:ATPase Inhibitory Protein