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Gene Review

MT-ATP6  -  mitochondrially encoded ATP synthase 6

Homo sapiens

Synonyms: ATP synthase F0 subunit 6, ATP synthase subunit a, ATP6, ATPASE6, ATPase-6, ...
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Disease relevance of MT-ATP6


High impact information on MT-ATP6

  • Two atp6 genes were found in the mitochondrial genome of cytoplasmic male sterile (CMS) rice carrying the [cms-bo] cytoplasm [6].
  • Here, we show in rice (Oryza sativa) with Boro II cytoplasm that an abnormal mitochondrial open reading frame, orf79, is cotranscribed with a duplicated atp6 (B-atp6) gene and encodes a cytotoxic peptide [7].
  • According to analysis by mass spectrometry, only one form of ATP6 protein accumulates in mitochondria despite the presence of abundant partially edited transcripts [8].
  • Transcripts encoding ATP synthase subunit 6 (ATP6) in petunia mitochondria were shown to be edited at 15 sites, leading to 14 amino acid changes [8].
  • Partially edited atp6 transcripts were associated with ribosomes, suggesting that a screening mechanism(s) acts cotranslationally or post-translationally to exclude the expression of incompletely edited transcripts [8].

Chemical compound and disease context of MT-ATP6

  • RNA editing and NH2-terminal processing of subunit 6 (atp6) of the mitochondrial Fo-ATPase complex has been investigated for the normal (fertile) and Ogura (male-sterile) radish cytoplasms to determine if previously identified differences between the Ogura atp6 locus and its normal radish counterpart are associated with cytoplasmic male sterility [9].
  • This gives strong support to the relevance of MTATP6 dysfunction in Leigh syndrome and the importance of leucine at that position [10].
  • We analyzed 11 spots, which were identified by mass spectrometry: Superoxide dismutase, alpha-crystallin-chain-B, mitochondrial stress protein, Mn SOD, ATP synthase A chain heart isoform, creatine kinase, and troponin T. All of these proteins were significantly decreased in the vehicle group when we compared to sham-treated animals [11].

Biological context of MT-ATP6

  • Analysis of amino acid substitution mutations (nonsynonymous, Ka) versus neutral mutations (synonymous, Ks) (kaks) for all 13 mtDNA protein-coding genes revealed that the ATP6 gene had the highest amino acid sequence variation of any human mtDNA gene, even though ATP6 is one of the more conserved mtDNA proteins [12].
  • Using sequences from four mitochondrial genes (12S, ATP8, ATP6, and ND6), we reconstructed the phylogeny of the Neotropical forest hawk genus Leucopternis and most of the allied genera of Neotropical buteonines [13].
  • In patient 1, with a mild and reversible phenotype, mutational analysis revealed a heteroplasmic T --> C mutation at nt position 9185 (T9185C) in the MTATP6 [4].
  • By quantifying the F1 subcomplexes and other oxidative phosphorylation complexes in parallel, we were able to discriminate three classes of defects in mitochondrial biosynthesis, namely, mitochondrial DNA depletion, mitochondrial transfer RNA (tRNA) mutations, and mutations in the mitochondrial ATP6 gene [14].
  • In spite of the evolutionary distance between algae and mammals, C. reinhardtii ATPase 6 functioned in human cells, because deficiencies in both cell viability and ATP synthesis in transmitochondrial cell lines harboring a pathogenic mutation in the human mtDNA-encoded ATP6 gene were overcome by expression of CrATP6 [15].

Anatomical context of MT-ATP6

  • This latter tumor also contained a germ-line ATP6 mutation [1].
  • No mutated mtDNA was detected in muscle and lymphocytes from the maternal grandmother of the proband or in lymphocytes from 15 other maternal relatives, showing that the first carrier of the ATP6 T8993G mutation in this family was the mother of the proband [16].
  • This phenotype markedly differs from the severe central nervous system changes of ATP synthase disorders caused by mitochondrial DNA mutations of the ATP6 gene presenting mostly as NARP and MILS [17].
  • The gene atp6, encoding subunit 6 of the mitochondrial F0-ATPase complex, has been characterized from both the normal (fertile) and Ogura (male-sterile) radish cytoplasms in order to determine if previously identified atp6 transcriptional differences could play a role in cytoplasmic male sterility [18].
  • PCR analysis around the atp6 gene demonstrated that inter-parental recombination occurs in practically all cybrid calli within 2 weeks after protoplast fusion [19].

Associations of MT-ATP6 with chemical compounds

  • A maternally inherited and practically homoplasmic mitochondrial (mtDNA) mutation, 8527A>G, changing the initiation codon AUG into GUG, normally coding for a valine, was observed in the ATP6 gene encoding the ATPase subunit a [20].
  • The substitution per site of ATP6, the proton conducting subunit of ATPsynthase, CYTB, the core subunit of ubiquinone oxidoreductase that participate in both electron and proton transport, and ND3, a subunit of NADH dehydrogenase, showed the strongest correlations with longevity [21].
  • It has been found that ALCAR treatment is able to upregulate the expression level of mitochondrial transcripts (COX I, ATP6, ND6, 16 S rRNA) in both control and unloaded animals [22].
  • Patient 2, with severe clinical phenotype and death at 2 years of age, exhibited a novel heteroplasmic T9191C missense mutation in the MTATP6, which converted a highly conserved leucine to a proline at position 222 of the polypeptide [4].
  • Mitochondrial DNA (mtDNA) fragments that contain cox2 and atp6 were cloned from a wild soybean (Glycine soja, accession 'B09002') and from a cultivated soybean (G. max, 'Harosoy') [23].

Other interactions of MT-ATP6

  • Absence of any mutations in mitochondrial ATP6 and ATP8 genes indicates a nuclear origin of the defect [24].
  • Northern Blot and quantitative real-time reverse transcription-PCR analysis further demonstrated that the primary ATP6--COX3 transcript is cleaved to the ATP6 and COX3 mRNAs 2-3-fold less efficiently [2].
  • RESULTS: Fourteen somatic mtDNA mutations were identified in 55% (11/20) of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively [25].
  • Comparison of the kaks ratios for each mtDNA gene from the tropical, temperate, and arctic zones revealed that ATP6 was highly variable in the mtDNAs from the arctic zone, cytochrome b was particularly variable in the temperate zone, and cytochrome oxidase I was notably more variable in the tropics [12].
  • Three of them were missense variants: MTCO2 7750C>A, MTATP6 8857G>A and MTND4 12096T>A [26].

Analytical, diagnostic and therapeutic context of MT-ATP6

  • This antibody did not recognize any ATP6 protein in either total mitochondrial protein preparations or ATP6 samples purified by organic solvent extraction and reverse phase HPLC procedures [8].
  • Electroporation of isolated higher-plant mitochondria: transcripts of an introduced cox2 gene, but not an atp6 gene, are edited in organello [27].
  • We now extend this correlation by showing that the effects of nuclear fertility restoration on orf224/atp6 transcripts cosegregate with the pol restorer gene Rfp1 in genetic crosses [28].
  • Southern blot analysis showed that the mitochondrial genome of CMS3 contains unique rearrangements in at least five loci (atp6, atp9, atpA, nad1 + 5 and coxIII) compared to the PET1 sterile and the fertile cytoplasms [29].
  • Among these, a primer pair at the 3' region of the atp6 gene (5'-cgcttggactatgctatgtatga-3') and the 5' region of the nad3 gene (5'-tcatagagaaatccaatcgtcaa-3') produced a 2 kbp DNA fragment as a result of PCR [30].


  1. mtDNA mutations increase tumorigenicity in prostate cancer. Petros, J.A., Baumann, A.K., Ruiz-Pesini, E., Amin, M.B., Sun, C.Q., Hall, J., Lim, S., Issa, M.M., Flanders, W.D., Hosseini, S.H., Marshall, F.F., Wallace, D.C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Diminished synthesis of subunit a (ATP6) and altered function of ATP synthase and cytochrome c oxidase due to the mtDNA 2 bp microdeletion of TA at positions 9205 and 9206. Jesina, P., Tesarová, M., Fornůsková, D., Vojtísková, A., Pecina, P., Kaplanová, V., Hansíková, H., Zeman, J., Houstek, J. Biochem. J. (2004) [Pubmed]
  3. ATP6 Homoplasmic Mutations Inhibit and Destabilize the Human F1F0-ATP Synthase without Preventing Enzyme Assembly and Oligomerization. Cort??s-Hern??ndez, P., V??zquez-Memije, M.E., Garc??a, J.J. J. Biol. Chem. (2007) [Pubmed]
  4. Two new mutations in the MTATP6 gene associated with Leigh syndrome. Moslemi, A.R., Darin, N., Tulinius, M., Oldfors, A., Holme, E. Neuropediatrics. (2005) [Pubmed]
  5. Cell type-specific loss of atp6 RNA editing in cytoplasmic male sterile Sorghum bicolor. Howad, W., Kempken, F. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  6. Processing followed by complete editing of an altered mitochondrial atp6 RNA restores fertility of cytoplasmic male sterile rice. Iwabuchi, M., Kyozuka, J., Shimamoto, K. EMBO J. (1993) [Pubmed]
  7. cytoplasmic male sterility of rice with boro II cytoplasm is caused by a cytotoxic peptide and is restored by two related PPR motif genes via distinct modes of mRNA silencing. Wang, Z., Zou, Y., Li, X., Zhang, Q., Chen, L., Wu, H., Su, D., Chen, Y., Guo, J., Luo, D., Long, Y., Zhong, Y., Liu, Y.G. Plant Cell (2006) [Pubmed]
  8. A single homogeneous form of ATP6 protein accumulates in petunia mitochondria despite the presence of differentially edited atp6 transcripts. Lu, B., Hanson, M.R. Plant Cell (1994) [Pubmed]
  9. Subunit 6 of the Fo-ATP synthase complex from cytoplasmic male-sterile radish: RNA editing and NH2-terminal protein sequencing. Krishnasamy, S., Grant, R.A., Makaroff, C.A. Plant Mol. Biol. (1994) [Pubmed]
  10. A point mutation of mitochondrial ATPase 6 gene in Leigh syndrome. Akagi, M., Inui, K., Tsukamoto, H., Sakai, N., Muramatsu, T., Yamada, M., Matsuzaki, K., Goto, Y., Nonaka, I., Okada, S. Neuromuscul. Disord. (2002) [Pubmed]
  11. Proteome analysis of myocardial tissue following ischemia and reperfusion-Effects of complement inhibition. Buerke, M., Schwertz, H., L??ngin, T., Buerke, U., Prondzinsky, R., Platsch, H., Richert, J., Bomm, S., Schmidt, M., Hillen, H., Lindemann, S., Blaschke, G., M??ller-Werdan, U., Werdan, K. Biochim. Biophys. Acta (2006) [Pubmed]
  12. Natural selection shaped regional mtDNA variation in humans. Mishmar, D., Ruiz-Pesini, E., Golik, P., Macaulay, V., Clark, A.G., Hosseini, S., Brandon, M., Easley, K., Chen, E., Brown, M.D., Sukernik, R.I., Olckers, A., Wallace, D.C. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  13. Polyphyly of the hawk genera Leucopternis and Buteogallus (Aves, Accipitridae): multiple habitat shifts during the Neotropical buteonine diversification. Amaral, F.S., Miller, M.J., Silveira, L.F., Bermingham, E., Wajntal, A. BMC Evol. Biol. (2006) [Pubmed]
  14. Subcomplexes of human ATP synthase mark mitochondrial biosynthesis disorders. Carrozzo, R., Wittig, I., Santorelli, F.M., Bertini, E., Hofmann, S., Brandt, U., Schägger, H. Ann. Neurol. (2006) [Pubmed]
  15. An algal nucleus-encoded subunit of mitochondrial ATP synthase rescues a defect in the analogous human mitochondrial-encoded subunit. Ojaimi, J., Pan, J., Santra, S., Snell, W.J., Schon, E.A. Mol. Biol. Cell (2002) [Pubmed]
  16. De novo mutation in the mitochondrial ATP synthase subunit 6 gene (T8993G) with rapid segregation resulting in Leigh syndrome in the offspring. Tulinius, M.H., Houshmand, M., Larsson, N.G., Holme, E., Oldfors, A., Holmberg, E., Wahlström, J. Hum. Genet. (1995) [Pubmed]
  17. Deficiency of mitochondrial ATP synthase of nuclear genetic origin. Sperl, W., Jesina, P., Zeman, J., Mayr, J.A., Demeirleir, L., Vancoster, R., P??ckov??, A., Hans??kov??, H., Houst'kov??, H., Krejc??k, Z., Koch, J., Smet, J., Muss, W., Holme, E., Houstek, J. Neuromuscul. Disord. (2006) [Pubmed]
  18. The atp6 coding region has been disrupted and a novel reading frame generated in the mitochondrial genome of cytoplasmic male-sterile radish. Makaroff, C.A., Apel, I.J., Palmer, J.D. J. Biol. Chem. (1989) [Pubmed]
  19. High-frequency inter-parental recombination between mitochondrial genomes of rice cybrids. Akagi, H., Shimada, H., Fujimura, T. Curr. Genet. (1995) [Pubmed]
  20. GUG is an efficient initiation codon to translate the human mitochondrial ATP6 gene. Dubot, A., Godinot, C., Dumur, V., Sablonnière, B., Stojkovic, T., Cuisset, J.M., Vojtiskova, A., Pecina, P., Jesina, P., Houstek, J. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  21. Longevity and the evolution of the mitochondrial DNA-coded proteins in mammals. Rottenberg, H. Mech. Ageing Dev. (2006) [Pubmed]
  22. Acetyl-l-carnitine feeding to unloaded rats triggers in soleus muscle the coordinated expression of genes involved in mitochondrial biogenesis. Cassano, P., Sciancalepore, A.G., Pesce, V., Fl??ck, M., Hoppeler, H., Calvani, M., Mosconi, L., Cantatore, P., Gadaleta, M.N. Biochim. Biophys. Acta (2006) [Pubmed]
  23. Small interspersed sequences that serve as recombination sites at the cox2 and atp6 loci in the mitochondrial genome of soybean are widely distributed in higher plants. Kanazawa, A., Tozuka, A., Kato, S., Mikami, T., Abe, J., Shimamoto, Y. Curr. Genet. (1998) [Pubmed]
  24. Reduced respiratory control with ADP and changed pattern of respiratory chain enzymes as a result of selective deficiency of the mitochondrial ATP synthase. Mayr, J.A., Paul, J., Pecina, P., Kurnik, P., Förster, H., Fötschl, U., Sperl, W., Houstek, J. Pediatr. Res. (2004) [Pubmed]
  25. Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer. Tan, D.J., Chang, J., Liu, L.L., Bai, R.K., Wang, Y.F., Yeh, K.T., Wong, L.J. BMC Cancer (2006) [Pubmed]
  26. New variants in the mitochondrial genomes of schizophrenic patients. Martorell, L., Segués, T., Folch, G., Valero, J., Joven, J., Labad, A., Vilella, E. Eur. J. Hum. Genet. (2006) [Pubmed]
  27. Electroporation of isolated higher-plant mitochondria: transcripts of an introduced cox2 gene, but not an atp6 gene, are edited in organello. Staudinger, M., Kempken, F. Mol. Genet. Genomics (2003) [Pubmed]
  28. Nuclear genes associated with a single Brassica CMS restorer locus influence transcripts of three different mitochondrial gene regions. Singh, M., Hamel, N., Menassa, R., Li, X.Q., Young, B., Jean, M., Landry, B.S., Brown, G.G. Genetics (1996) [Pubmed]
  29. Characterisation and expression of the mitochondrial genome of a new type of cytoplasmic male-sterile sunflower. Spassova, M., Moneger, F., Leaver, C.J., Petrov, P., Atanassov, A., Nijkamp, H.J., Hille, J. Plant Mol. Biol. (1994) [Pubmed]
  30. Development of a molecular marker specific to a novel CMS line in radish (Raphanus sativus L.). Nahm, S.H., Lee, H.J., Lee, S.W., Joo, G.Y., Harn, C.H., Yang, S.G., Min, B.W. Theor. Appl. Genet. (2005) [Pubmed]
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