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The enigmatic mitochondrial ORF ymf39 codes for ATP synthase chain b.

ABSTRACT: ymf39 is a conserved hypothetical protein-coding gene found in mitochondrial genomes of land plants and certain protists. We speculated earlier, based on a weak sequence similarity between Ymf39 from a green alga and the atpF gene product from Bradyrhizobium, that ymf39 might code for subunit b of mitochondrial F(0)F(1)-ATP synthase. To test this hypothesis, we have sequenced ymf39 from five protists with minimally derived mitochondrial genomes, the jakobids. In addition, we isolated the mitochondrial ATP synthase complex of the jakobid Seculamonas ecuadoriensis and determined the partial protein sequence of the 19-kDa subunit, the size expected for Ymf39. The obtained peptide sequence matches perfectly with a 3'-proximal region of the ymf39 gene of this organism, confirming that Ymf39 is indeed an ATP synthase subunit. Finally, we employed statistical tests to assess the significance of sequence similarity of Ymf39 proteins with each other, their nucleus-encoded functional counterparts, ATP4/ATP5F, from fungi and animals and alpha-proteobacterial ATP synthase b-subunits. This analysis provides clear evidence that ymf39 is an atpF homolog, while ATP4/ATP5F appears to be a highly diverged form of ymf39 that has migrated to the nucleus. We propose to designate ymf39 from now on atp4.

SUBMITTER: Burger G

PROVIDER: S-EPMC154212 | biostudies-literature | 2003 May

REPOSITORIES: biostudies-literature

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The enigmatic mitochondrial ORF ymf39 codes for ATP synthase chain b.

Burger Gertraud G Lang B Franz BF Braun Hans-Peter HP Marx Stefanie S

Nucleic acids research 20030501 9

ymf39 is a conserved hypothetical protein-coding gene found in mitochondrial genomes of land plants and certain protists. We speculated earlier, based on a weak sequence similarity between Ymf39 from a green alga and the atpF gene product from Bradyrhizobium, that ymf39 might code for subunit b of mitochondrial F(0)F(1)-ATP synthase. To test this hypothesis, we have sequenced ymf39 from five protists with minimally derived mitochondrial genomes, the jakobids. In addition, we isolated the mitocho ...[more]

PMID: 12711680

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Project description:The F-type ATP synthase complex is a rotary nano-motor driven by proton motive force to synthesize ATP. Its F(1) sector catalyzes ATP synthesis, whereas the F(o) sector conducts the protons and provides a stator for the rotary action of the complex. Components of both F(1) and F(o) sectors are highly conserved across prokaryotes and eukaryotes. Therefore, it was a surprise that genes encoding the a and b subunits as well as other components of the F(o) sector were undetectable in the sequenced genomes of a variety of apicomplexan parasites. While the parasitic existence of these organisms could explain the apparent incomplete nature of ATP synthase in Apicomplexa, genes for these essential components were absent even in Tetrahymena thermophila, a free-living ciliate belonging to a sister clade of Apicomplexa, which demonstrates robust oxidative phosphorylation. This observation raises the possibility that the entire clade of Alveolata may have invented novel means to operate ATP synthase complexes. To assess this remarkable possibility, we have carried out an investigation of the ATP synthase from T. thermophila. Blue native polyacrylamide gel electrophoresis (BN-PAGE) revealed the ATP synthase to be present as a large complex. Structural study based on single particle electron microscopy analysis suggested the complex to be a dimer with several unique structures including an unusually large domain on the intermembrane side of the ATP synthase and novel domains flanking the c subunit rings. The two monomers were in a parallel configuration rather than the angled configuration previously observed in other organisms. Proteomic analyses of well-resolved ATP synthase complexes from 2-D BN/BN-PAGE identified orthologs of seven canonical ATP synthase subunits, and at least 13 novel proteins that constitute subunits apparently limited to the ciliate lineage. A mitochondrially encoded protein, Ymf66, with predicted eight transmembrane domains could be a substitute for the subunit a of the F(o) sector. The absence of genes encoding orthologs of the novel subunits even in apicomplexans suggests that the Tetrahymena ATP synthase, despite core similarities, is a unique enzyme exhibiting dramatic differences compared to the conventional complexes found in metazoan, fungal, and plant mitochondria, as well as in prokaryotes. These findings have significant implications for the origins and evolution of a central player in bioenergetics.

Project description:ObjectiveATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases.MethodsWhole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients.ResultsWe present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10).InterpretationOur results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. ANN NEUROL 2022;91:225-237.

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The enigmatic mitochondrial ORF ymf39 codes for ATP synthase chain b.

Publications

The enigmatic mitochondrial ORF ymf39 codes for ATP synthase chain b.

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