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Big Consequences of a Little Carry-over in Mitochondrial Replacement Therapy

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Review of “Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes” from Cell Stem Cell by Stuart P. Atkinson

Recent studies have provided evidence that oocyte mitochondrial replacement therapy may represent an effective means to halt the transmission of diseases caused by mutations in the mitochondrial (mt)DNA. However, mutant-bearing mitochondria remain in small numbers, and the consequences of this “carry-over” are, at present, unknown.

To this end, researchers from the laboratory of Michio Hirano and Dieter Egli have recently studied nuclear transfer techniques and embryonic stem cell (ESC) derivation. Their Cell Stem Cell brief report finds that even a small percentage of mitochondrial carry-over can have big consequences: mtDNA reversion and the reappearance of mtDNA disease [1].

Initial studies transferred nuclear genomes between oocytes of women with different mitochondrial haplotypes followed by parthenogenesis (to exclude potential functional complementation by paternal nuclear alleles). ESCs derived from resultant blastocysts maintained a very low level of mitochondrial heteroplasmy (~0-2%), except for one of the 8 studied lines, whose heteroplasmy levels rose to over 50% before returning to around 1% during extended culture. Interestingly, clonal expansion of single cells taken at various passage numbers from this ESC line further demonstrated an unpredictable drift in mitochondrial heteroplasmy.

When the authors then assessed ESCs derived from somatic cell nuclear genome transfer into human oocytes, the strategy employed for the proposed mitochondrial replacement therapy, they also found drifts in mitochondrial heteroplasmy. Indeed, one ESC line quickly achieved homoplasmic levels of the “unwanted” original donor mtDNA, and overall, 3 of 24 ESC lines displayed mtDNA genotype instability which remained even after ESC differentiation.

The study did not, however, delineate the mechanisms which cause the drift, although the study did find that changes in cell survival, proliferation, mitochondrial function, or competitive advantages provided by specific mitochondrial-nuclear DNA combinations did not contribute significantly to mitochondrial heteroplasmic drift.

While this study does suggest that mitochondrial replacement therapy can work, mitochondrial heteroplasmic drifting can occur, leading to the restoration of the original donor mitochondrial genotype. Big consequences of a little carry-over!

Since the publication of this study, Hyslop et al confirmed these findings [2], concluding that conclude nuclear transfer “has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention”. Further work will hopefully answer some of the unanswered questions; how does mitochondrial drift occur, can we predict if it is likely to occur, and can we artificially inhibit drift occurring?

References

  1. Yamada M, Emmanuele V, Sanchez-Quintero MJ, et al. Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes. Cell Stem Cell 2016;18:749-754.
  2. Hyslop LA, Blakeley P, Craven L, et al. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature 2016;534:383-386.