Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus
@article{Manfredi2002RescueOA, title={Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus}, author={Giovanni Manfredi and Jin Fu and Joseline Ojaimi and James E. Sadlock and Jennifer Q Kwong and John R Guy and Eric A. Schon}, journal={Nature Genetics}, year={2002}, volume={30}, pages={394-399} }
A T→G transversion at nt 8993 in mitochondrial DNA of MTATP6 (encoding ATPase 6 of complex V of the respiratory chain) causes impaired mitochondrial ATP synthesis in two related mitochondrial disorders: neuropathy, ataxia and retinitis pigmentosa and maternally inherited Leigh syndrome. To overcome the biochemical defect, we expressed wildtype ATPase 6 protein allotopically from nucleus-transfected constructs encoding an amino-terminal mitochondrial targeting signal appended to a recoded ATPase…
260 Citations
Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or v subunits.
- BiologyRejuvenation research
- 2007
This study shows that allotopic expression of a recoded ATP6 gene leads to a long-lasting and complete rescue of mitochondrial dysfunction of fibroblasts harboring the neurogenic muscle weakness, ataxia and retinitis Pigmentosa T8993G ATP6 mutation or the Leber hereditary optic neuropathy G11778A ND4 mutation.
Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant
- BiologyNucleic acids research
- 2016
Tests for ATP hydrolysis / synthesis, oxygen consumption, glycolytic metabolism and viability all indicate a significant functional rescue of the mutant phenotype (including re-assembly of Complex V) following stable co-expression of ATP8 and ATP6.
What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes.
- BiologyMitochondrion
- 2011
Limitations of allotopic expression of mitochondrial genes in mammalian cells.
- BiologyGenetics
- 2003
Allotopic expression of apocytochrome b and ND4 induced a loss of mitochondrial membrane potential in transfected cells, which can lead to cell death, andalyses of the hydrophobic patterns of different polypeptides suggest that hydrophobicity of the N-terminal segment is the main determinant for the importability of peptides into mammalian mitochondria.
An algal nucleus-encoded subunit of mitochondrial ATP synthase rescues a defect in the analogous human mitochondrial-encoded subunit.
- BiologyMolecular biology of the cell
- 2002
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.
Optimized Mitochondrial Targeting of Proteins Encoded by Modified mRNAs Rescues Cells Harboring Mutations in mtATP6.
- BiologyCell reports
- 2018
Expression of algal nuclear ATP synthase subunit 6 in human cells results in protein targeting to mitochondria but no assembly into ATP synthase.
- BiologyRejuvenation research
- 2006
Nuclear compatible versions of human subunit a (A6) of ATP synthase, linked to a mitochondrial targeting signal are created, finding obstacles remain to functional expression of mitochondrial genes transferred to the nucleus.
Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy
- BiologyAnnals of neurology
- 2002
Restoration of respiration by allotopic expression opens the door for gene therapy of Leber Hereditary Optic Neuropathy by correcting a defect in the mitochondrial genome linked to a human disease.
RNA-mediated restoration of mitochondrial function in cells harboring a Kearns Sayre Syndrome mutation.
- BiologyMitochondrion
- 2011
Protein coding mitochondrial-targeted RNAs rescue mitochondrial disease in vivo
- BiologyNeurobiology of Disease
- 2018
References
SHOWING 1-10 OF 46 REFERENCES
Oligomycin Induces a Decrease in the Cellular Content of a Pathogenic Mutation in the Human Mitochondrial ATPase 6 Gene*
- BiologyThe Journal of Biological Chemistry
- 1999
This work created selective culture conditions using galactose and oligomycin that elicited a pathological phenotype in T8993G cells and that allowed for the rapid selection of wild-type over T9003G mutant cells, and showed that selection in Galactose-oligomycin caused a significant increase in the fraction ofWild-type molecules in these cells.
Studies on the import into mitochondria of yeast ATP synthase subunits 8 and 9 encoded by artificial nuclear genes
- Biology, ChemistryFEBS letters
- 1988
Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA
- BiologyNature Medicine
- 2001
Inter-mitochondrial complementation shows a mitochondria-specific mechanism for avoiding expression of deletion-mutant mtDNA, and opens the possibility of a gene therapy in which mitochondria possessing full-length DNA are introduced.
The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria.
- Biology, ChemistryBiochemical and biophysical research communications
- 1993
This mutation which changes a conserved leucine to an arginine in the putative membrane proton channel of mitochondrial ATPase effectively reduces the overall rate of oxidative phosphorylation.
Allotopic expression of mitochondrial ATP synthase genes in nucleus of Saccharomyces cerevisiae.
- BiologyMethods in enzymology
- 1996
Pathogenesis of primary defects in mitochondrial ATP synthesis.
- BiologySeminars in cell & developmental biology
- 2001
A model is proposed that may help explain why mutations at codons 156 and 217 are pathogenic, which can suffer mutations converting a conserved leucine to either an arginine or a proline.
Structure, Functioning, and Assembly of the ATP Synthase in Cells from Patients with the T8993G Mitochondrial DNA Mutation
- Biology, ChemistryThe Journal of Biological Chemistry
- 2000
It is concluded that the loss of ATP synthesis is because of disruption of the proton translocation step within the F0 part, and this much reduced effect for only a 9% difference in mutation load mirrors the reduced pathogenicity in patients.
Mitochondrial DNA of two independent oligomycin-resistant Chinese hamster ovary cell lines contains a single nucleotide change in the ATPase 6 gene.
- Biology, ChemistryThe Journal of biological chemistry
- 1986
Processing of Artificial Peptide-DNA-Conjugates by the Mitochondrial Intermediate Peptidase (MIP)
- Biology, ChemistryBiological chemistry
- 1999
Results show that artificial peptide-DNA-conjugates are recognized by the mitochondrial proteolytic machinery, and therefore an interference of the peptide with the DNA function can be excluded.