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Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus

Nature Geneticsvolume 30pages394399 (2002) | Download Citation



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 pigmentosa1 and maternally inherited Leigh syndrome2. To overcome the biochemical defect, we expressed wildtype ATPase 6 protein allotopically3 from nucleus-transfected constructs encoding an amino-terminal mitochondrial targeting signal appended to a recoded ATPase 6 gene (made compatible with the universal genetic code) that also contained a carboxy-terminal FLAG epitope tag. After transfection of human cells, the precursor polypeptide was expressed, imported into and processed within mitochondria, and incorporated into complex V. Allotopic expression of stably transfected constructs in cytoplasmic hybrids (cybrids) homoplasmic with respect to the 8993T→G mutation showed a significantly improved recovery after growth in selective medium as well as a significant increase in ATP synthesis. This is the first successful demonstration of allotopic expression of an mtDNA-encoded polypeptide in mammalian cells and could form the basis of a genetic approach to treat a number of human mitochondrial disorders.

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We thank S. Goff and E. Bacharach for advice and H. Du for technical assistance. This work was supported by grants from the US National Institutes of Health (to G.M., E.A.S. and J.G.) and the Muscular Dystrophy Association (to E.A.S. and G.M.).

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Author notes

    • Jin Fu

    Present address: University of California, Irvine, California, USA

    • James E. Sadlock

    Present address: Roche Molecular Biochemicals, Indianapolis, Indiana, USA


  1. Department of Neurology and Neuroscience, Cornell University, New York, New York, USA

    • Giovanni Manfredi
    •  & Jennifer Q. Kwong
  2. Department of Neurology, Room 4-431, Columbia University, 630 West 168th Street, New York, 10032, New York, USA

    • Jin Fu
    • , Joseline Ojaimi
    • , James E. Sadlock
    •  & Eric A. Schon
  3. Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, USA

    • John Guy
  4. Department of Genetics and Development, Columbia University, New York, New York, USA

    • Eric A. Schon


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The authors declare no competing financial interests.

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Correspondence to Eric A. Schon.

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