PMID:20566710

Citation	Mayr, JA, Havlícková, V, Zimmermann, F, Magler, I, Kaplanová, V, Jesina, P, Pecinová, A, Nusková, H, Koch, J, Sperl, W and Houstek, J (2010) Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum. Mol. Genet. 19:3430-9
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.
Links	PubMed Online version:10.1093/hmg/ddq254
Keywords	Amino Acid Sequence; Base Sequence; Cells, Cultured; Female; Fibroblasts/chemistry; Fibroblasts/enzymology; Humans; Mitochondrial Diseases/enzymology; Mitochondrial Diseases/genetics; Mitochondrial Proton-Translocating ATPases/deficiency; Mitochondrial Proton-Translocating ATPases/genetics; Molecular Sequence Data; Mutation, Missense; Proteins/chemistry; Proteins/genetics; Proteins/metabolism; Sequence Alignment; Young Adult
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:ATP5E		GO:0000275: mitochondrial proton-transporting ATP synthase complex, catalytic core F(1)	ECO:0000315:		C		In the paragraph labeled "Low content of ATP synthase subunit ε, but increased content of subunit c is present in patient mitochondria". Figure 6 shows the patient mitochondria with accumulated Fo subunit c of ATP synthase. Figure 5 shows a mutated subunit ε is incorporated in the ATP synthase complex.	complete CACAO 3740
HUMAN:ATP5E	part_of	GO:0000275: mitochondrial proton-transporting ATP synthase complex, catalytic core F(1)	ECO:0000315: mutant phenotype evidence used in manual assertion		C		Seeded From UniProt	complete

References

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