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Matching mitochondrial and nuclear DNA: Much ado about nothing?

18 July 2016
By Dr Dusko Ilic
Dusko Ilic, Assisted Conception Unit, Guy's Hospital, London
Appeared in BioNews 860

Science is not immune to fashion. Some research topics are trendier and sexier than others. Though, not forever. In a few years they will be replaced with something else. Fashion-conscious scientists will recognise trends early and quickly jump on the bandwagon, re-dress their research into new clothing, and publish ASAP. Subsequent publications in the trendy field will thrust the scientist into the limelight and ensure grant money for a few coming years.

The UK was the first country in the world to legislate for the conception of babies using genetic material from three people, including one set which provides healthy mitochondria. Since then, almost anything to do with mitochondria and nuclear transfer has ended up in journals with double digit impact factor, and have also triggered press releases which are, unsurprisingly, caught by the media.

The latest example is the work of scientists from the University of Santiago de Compostela, Spain, which was published in Nature. They came up with an amazing concept – showing that a specific match of mitochondrial and nuclear genomes results in healthier ageing and longevity (see BioNews 859). How did they achieve this? They worked on two strains of highly inbred mice: C57BL/6 and the NZB/OlaHsd. They generated a conplastic strain – mice containing a nuclear genome from one individual and mitochondria from another; in this case C57BL/6 nuclear genome and NZB/OlaHsd mitochondria. The new conplastic strain had an extended median lifespan and altogether was healthier than the original C57BL/6 strain, as demonstrated by measuring multiple parameters including age-related health decline, weight gain, and blood sugar fluctuations.

Irritatingly enough, the abstract and discussion focused on concerns about 'implications for the emerging new field of mitochondrial replacement therapy in human oocytes'. I can bet that this paper would not have made it into Nature a couple years ago, before 'three-parent babies' became media darlings.

Should the 'emerging new field of mitochondrial replacement therapy in human oocytes' be concerned about the reported findings? I do not think so. The conclusions were based on only one example of a highly inbred mouse strain. Although I found the concept quite intriguing and would like to see more work on this, the lack of the data from obvious controls, the claims, and the overstated conclusions, made this rather observational report pretty dismissive.

We do not even know whether NZB/OlaHsd mice with their original nuclear and mitochondrial genomes have longer and healthier lives than C57BL/6 mice. If the NZB/OlaHsd mitochondrial genome is better because it produces mitochondria that are more metabolically active, NZB/OlaHsd mice should be comparable to a conplastic strain containing the C57BL/6 nuclear genome and NZB/OlaHsd mitochondria. And vice versa, replacing highly active NZB/OlaHsd mitochondria with sluggishly performing C57BL/6 mitochondria should negatively affect the lifespan of the NZB/OlaHsd strain. Only then could I buy some of the claims made in the paper.

For the sake of argument, let us say that they did the experiment and demonstrated that C57BL/6 mitochondria did worsen ageing of NZB/OlaHsd mice. There is still the issue of inbreeding. Mice, and not only mice, are highly diverse. Would more metabolically active NZB/OlaHsd mitochondria have such beneficial effects in naturally bred wild mice? Inbreeding could lead to two distinct possibilities: 1) Due to inbreeding, we unwittingly selected NZB/OlaHsd mitochondria that are more metabolically active in general, not only in comparison with another inbred strain C57BL/6, or 2) Even though they performed better than C57BL/6 mitochondria, NZB/OlaHsd mitochondria are still acting sluggishly in comparison with mitochondria from wild type mice.

If the first possibility is correct, should we isolate mitochondria from families known for long healthy lifespans, and try to multiply them in cell lines so we can provide future IVF patients with a carefully selected set of mitochondria that could promise their baby a long healthy life? Sounds a bit iffy. Though, I might be wrong. There is already a business out there claiming that supplementing a women’s mature eggs with added mitochondria will improve embryo development and IVF success. More mitochondria equal more energy, whether their performance is sluggish or not, and that will lead to better quality eggs.

If the second possibility is correct, then we do not need to worry at all. Humans are highly outbred, not inbred, and all such claims will have only anecdotal value.

As a proverb says: 'The dogs bark but the caravan moves on.'

Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing
Nature |  6 July 2016
22 August 2016 - by Dr Özge Özkaya 
Chinese researchers say an IVF technique called pronuclear transfer can safely produce a viable pregnancy...
11 July 2016 - by Dr Julia Hill 
The interaction between mitochondrial and nuclear DNA may have implications for health, metabolism and ageing, according to a new study...
13 June 2016 - by Dr Özge Özkaya 
An extensive study examining human embryos created using mitochondrial donation has demonstrated that the technique does not adversely affect embryo development...
25 April 2016 - by Dr Julia Hill 
A study has found that stem cells from older people accumulate high numbers of mitochondrial DNA mutations, which could limit their therapeutic value...
8 February 2016 - by Kirsty Oswald 
Clinical investigations of mitochondrial donation are 'ethically permissable', says a panel of experts reporting to the US Food and Drug Administration...
11 January 2016 - by Dr Cathy Herbrand 
We report from the second session of the annual conference of the Progress Educational Trust, titled 'From Three-Person IVF to Genome Editing: the Science and the Ethics of Engineering the Embryo', about the newly legalised process of mitochondrial donation...
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