Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear respiratory-deficient mutants of Saccharomyces cerevisiae (pet mutants) have been screened for defects in the mitochondrial ATPase. Mutants in two complementation groups were found to have 10% or less of wild-type ATPase activity. The two wild-type nuclear genes defined by the mutants have been designated ATP11 and ATP12. The proteins encoded by the two genes are not subunits of the ATPase but rather appear to exercise an important function at a late stage in the synthesis of F1 after transport of the subunits into the internal compartment of mitochondria. Mitochondria of atp11 and atp12 mutants have only marginally reduced levels of the alpha and beta subunits of F1. Both proteins are processed to their mature size but are not part of a native F1 structure or associated with the mitochondrial membrane. The most reasonable explanation for the mutant phenotype is a block in the assembly of the F1 oligomer.
 ...
PMID:Identification of two nuclear genes (ATP11, ATP12) required for assembly of the yeast F1-ATPase. 214 5

Atp11p (Atpaf1p; F(1)-ATPase assembly factor 1) and Atp12p (Atpaf2p; F(1)-ATPase assembly factor 2) are proteins required for the assembly of beta (F(1)-beta) and alpha (F(1)-alpha) subunits into the mitochondrial ATPase. Here we report about 100 times lower levels of ATPAF1 and ATPAF2 transcripts in relation to the mRNA levels of F(1)-alpha and F(1)-beta in a range of mouse tissues. Quantitative reverse-transcription polymerase chain reaction revealed nearly constant ATPAF1 expression in all tissues in both adult and 5-day-old mice (up to two-fold differences), indicating that ATPAF1 rather behaves like a maintenance gene. In contrast, ATPAF2 expression differed up to 30-fold in the tissues analysed. ATPAF2 tissue-specific expression was also found to correlate well with mRNA levels of both F(1)-alpha and F(1)-beta (BATz.Gt;kidney, liver>heart, brain>skeletal muscle), showing the highest mRNA level in the thermogenic, ATPase-poor brown adipose tissue, which is characterised by a 10-fold decrease in ATPase/respiratory chain stoichiometry relative to the other tissues.
 ...
PMID:Differential expression of ATPAF1 and ATPAF2 genes encoding F(1)-ATPase assembly proteins in mouse tissues. 1296 2

In patients with mitochondrial encephalomyopathies an increasing number of causative gene defects have been detected. The number of identified pathogenic mitochondrial DNA mutations has largely increased over the past 15 years. Recently, much attention has turned to the investigation of nuclear oxidative phosphorylation (OXPHOS) gene defects. Within the OXPHOS defects, complex V deficiency is rarely found and, so far, these defects have only been attributed to mutations in the mitochondrial MTATP6 gene. Mutation analysis of the complete coding regions at the cDNA level of the nuclear ATP11, ATP12, ATPalpha, ATPbeta and ATPgamma genes and the mitochondrial MTATP6 and MTAT8 genes was undertaken in two unrelated patients. Blue Native polyacrylamide gel electrophoresis followed by catalytic staining had already documented their complex V decreased activity. Extensive molecular analysis of five nuclear and two mitochondrial genes revealed a mutation in the ATP12 assembly gene in one patient. This mutation is believed to be the cause of the impaired complex V activity. To our knowledge, this is the first report of a pathogenic mutation in a human nuclear encoded ATPase assembly gene.
 ...
PMID:Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. 1475 59

The mitochondrial F(1)F(0)-ATP synthase or ATPase is a key enzyme for aerobic energy production in eukaryotic cells. Mutations in ATPase structural and assembly genes are the primary cause of severe human encephalomyopathies, frequently associated with a pleiotropic decrease in cytochrome c oxidase (COX) activity. We have studied the structural and functional constraints underlying the COX defect using Saccharomyces cerevisiae genetic and pharmacological models of ATPase deficiency. In both yeast Deltaatp10 and oligomycin-treated wild type cells, COX assembly is selectively impaired in the absence of functional ATPase. The COX biogenesis defect does not involve a primary alteration in the expression of the COX subunits as previously suggested but in their maturation and/or assembly. Expression of COX subunit 1, however, is translationally regulated as in most bona fide COX assembly mutants. Additionally, the COX defect in oligomycin-inhibited ATPase-deficient yeast cells, but not in atp10 cells could be partially prevented by partially dissipating the mitochondrial membrane potential using the uncoupler CCCP. Similar results were obtained with oligomycin-treated and ATP12-deficient human fibroblasts respectively. Our findings imply that fully assembled ATPase and its proton pumping function are both required for COX biogenesis in yeast and mammalian cells through a mechanism independent of Cox1p synthesis.
 ...
PMID:Synthesis of cytochrome c oxidase subunit 1 is translationally downregulated in the absence of functional F1F0-ATP synthase. 1973 76

Studies in yeast have shown that a deficiency in Atp12p prevents assembly of the extrinsic domain (F(1)) of complex V and renders cells unable to make ATP through oxidative phosphorylation. De Meirleir et al. (De Meirleir, L., Seneca, S., Lissens, W., De Clercq, I., Eyskens, F., Gerlo, E., Smet, J., and Van Coster, R. (2004) J. Med. Genet. 41, 120-124) have reported that a homozygous missense mutation in the gene for human Atp12p (HuAtp12p), which replaces Trp-94 with Arg, was linked to the death of a 14-month-old patient. We have investigated the impact of the pathogenic W94R mutation on Atp12p structure/function. Plasmid-borne wild type human Atp12p rescues the respiratory defect of a yeast ATP12 deletion mutant (Deltaatp12). The W94R mutation alters the protein at the most highly conserved position in the Pfam sequence and renders HuAtp12p insoluble in the background of Deltaatp12. In contrast, the yeast protein harboring the corresponding mutation, ScAtp12p(W103R), is soluble in the background of Deltaatp12 but not in the background of Deltaatp12Deltafmc1, a strain that also lacks Fmc1p. Fmc1p is a yeast mitochondrial protein not found in higher eukaryotes. Tryptophan 94 (human) or 103 (yeast) is located in a positively charged region of Atp12p, and hence its mutation to arginine does not alter significantly the electrostatic properties of the protein. Instead, we provide evidence that the primary effect of the substitution is on the dynamic properties of Atp12p.
 ...
PMID:Defining the pathogenesis of the human Atp12p W94R mutation using a Saccharomyces cerevisiae yeast model. 1993 71

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.
 ...
PMID:Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. 2056 10

The mammalian mitochondrial ATP synthase, also as known as mitochondrial respiratory chain complex V, is a large protein complex located in the mitochondrial inner membrane, where it catalyzes ATP synthesis from ADP, Pi, and Mg2+ at the expense of an electrochemical gradient of protons generated by the electron transport chain. Complex V is composed of 2 functional domains F0 and F1. The clinical features of patients are significantly heterogeneous depending on the involved organs. Most patients with complex V deficiency had clinical onset in the neonatal period with severe brain damage or multi-organ failure resulting in a high mortality. Neuromuscular disorders, cardiomyopathy, lactic acidosis and 3-methylglutaconic aciduria are common findings. Complex V consists of 16 subunits encoded by both mitochondrial DNA and nuclear DNA. On MT-ATP6, MT-ATP8, ATPAF2, TMEM70 and ATP5E gene of mitochondrial DNA, many mutations associated with Complex V deficiency have been identified. Here, the pathology, clinical features, diagnosis, treatment and molecular genetics of Complex V deficiency were summarized.
...
PMID:[Mitochondrial disorders associated with mitochondrial respiratory chain complex V deficiency]. 2386 88