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Inter-mitochondrial complementation of mtDNA mutations and nuclear context

Nature Genetics volume 30, page 360 (2002)Cite this article

Ono et al.1 report extensive inter- mitochondrial complementation (transcomplementation) in cell hybrids between two types of respiratory-deficient mitochondria carrying either of two human mtDNA pathogenetic recessive mutations in the genes for tRNAIle and tRNALeu(UUR). Nearly all the hybrids exhibited normal mitochondrial protein synthesis and respiratory activity 10 to 14 days after fusion, but not earlier. Their results are in striking contrast with our previous observations2,3, which indicated clearly that complementation between two different deleterious mtDNA mutations carried within distinct organelles in the same human cell could indeed occur, but was a rare phenomenon in the cells analyzed. We wish to point out that the discrepancy between the conclusions of the two laboratories does not concern the issue of whether mammalian mitochondria have the potential to fuse and mix their mtDNA and/or mtDNA products in vivo, an issue on which we do not disagree, but which rather has to do with the generality and frequency of this phenomenon and the importance of its control by the nucleus.

Ono et al.1 attributed our results of low frequency of transcomplementation to the slow recovery of respiration in the fused parental cells and to their early exposure to conditions selective for respiration. The data, however, do not support this interpretation. In fact, in our first study2, in which mitochondria carrying either one of two recessive tRNA mutations were brought together in the same cell, the cells were kept under conditions that do not select for respiration. The clones that contained both mutated mtDNAs, first analyzed 42–99 days after fusion, all showed a marginal rate of mitochondrial protein synthesis and no recovery of respiration capacity. On the other hand, in a second, large-scale investigation3, the relatively small fraction of transcomplementing clones (representing less than 1% of the fusion products), isolated after only 1- or 2-day incubation in nonselective medium, exhibited full restoration of respiration, and there was no increase in their frequency after 6 days of growth in nonselective medium. It is therefore implausible that extending the period of growth in this medium to 10–14 days would lead to anything close to the 100% frequency observed by Ono et al.1

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Authors and Affiliations

  1. Division of Biology, California Institute of Technology, Pasadena, 91125, California, USA

    Giuseppe Attardi

  2. Departamento de Bioquimica y Biologia Molecular y Celular, Universidad de Zaragoza, Zaragoza, 50013, Spain

    José A. Enriquez

  3. Departamento de Bioquimica y Biologia Molecular A., Universidad de Murcia, Murcia, 30071, Spain

    Juan Cabezas-Herrera

Authors
  1. Giuseppe Attardi
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  2. José A. Enriquez
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  3. Juan Cabezas-Herrera
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Correspondence to Giuseppe Attardi.

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Attardi, G., Enriquez, J. & Cabezas-Herrera, J. Inter-mitochondrial complementation of mtDNA mutations and nuclear context. Nat Genet 30, 360 (2002). https://doi.org/10.1038/ng0402-360

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