Mitochondria variants battle for cell supremacy

Some mitochondria naturally have an advantage over others in the battle for cellular domination, a new study shows. The finding could make procedures for producing “three-parent babies” safer.

Doctors carrying out DNA-swapping techniques to prevent mothers from passing mitochondrial diseases to their children should choose egg donors whose mitochondria can hold their own against other varieties or even outcompete them, researchers propose November 30 in Nature.  Such a precaution might prevent small numbers of faulty mitochondria — energy-generating organelles — from taking over cells.

More than 750 babies are estimated to be born in the United States each year with mutations in their mitochondrial DNA that may lead to disabling or fatal diseases. Researchers have developed techniques to swap DNA from a mother’s egg with faulty mitochondria into a donor egg containing healthy mitochondria (SN Online: 10/18/16). One apparently healthy baby has already been born using a “mitochondrial replacement therapy” procedure called spindle transfer (SN Online: 9/27/16).

But researchers have previously shown that a small number of mitochondria carried over from a mother’s egg could replace the donor egg’s mitochondria, potentially reversing the effect of the treatment (SN: 6/25/16, p. 8). Those studies were done with healthy mitochondria, and researchers questioned whether mutant mitochondria could really outcompete healthy ones — a process called “reversion,” says Dieter Egli, a reproductive biologist at Columbia University Medical Center, who conducted this earlier study.

In the new study, four women who carry a mitochondrial disease called Leigh syndrome and 11 volunteers with healthy mitochondria donated eggs. All of the women had naturally occurring genetic variants in a small portion of the mitochondrial DNA called the D loop. The variants, called haplotypes, are harmless, but enable researchers to tell one type of mitochondria from another. An international team of researchers led by mitochondrial biologist Shoukhrat Mitalipov of Oregon Health & Science University in Portland tested different combinations of mitochondrial haplotypes to determine whether some types are more prone to overtaking a cell. The experiments included spindle transfers between healthy eggs and from Leigh syndrome eggs into healthy eggs.

In most cases, 1 percent or fewer of mitochondria in the donor egg were carried over from the mom’s egg. Those remnant mitochondria usually stayed at low levels, and the donor egg mitochondria remained the dominant type in the cells. In a few cases, though, as stem cells made from the embryos grew in lab dishes, the mother’s mitochondrial DNA — including some that carried Leigh syndrome mutations — began to take over.

Mitalipov and colleagues examined the mitochondrial DNA and found that some variants in the D loop allow the DNA to replicate faster and dominate slower replicating varieties. That happened even when the faster replicator contained a disease-causing mutation elsewhere. In other cases, both the mom’s and the donor’s mitochondrial DNA replicated at the same rate, but certain varieties of mitochondria gave cells a growth advantage. Those growth advantages are probably due to genes in the nucleus, which include ones that control mitochondrial growth. The researchers aren’t sure what mechanism produces the boost. Cells that got a growth boost contained mitochondria from two healthy donors, and the researchers don’t know whether mutant mitochondria could also give a growth advantage.

It’s also not clear whether the takeovers could actually happen in a developing embryo, or if they are a consequence of growing cells in a lab dish, Mitalipov says. He has conducted spindle transfer on macaques and mice and none show evidence of low-abundance mitochondria staging a coup to become the predominant type in the body.

Regulators considering whether to allow clinical trials of mitochondrial replacement therapy had asked Mitalipov and colleagues whether doctors would need to match the mitochondrial haplotype from the mother to that of the donor. “The answer was always, ‘We don’t know,’” he says. But the new data indicate that proper reply is “yes.”

Mitalipov’s Oregon colleague Paula Amato said the researchers propose a mitochondria matching strategy, similar to tissue-type matching done for organ donations, to ensure that donor mitochondrial DNA will come out on top. 

Even with matching strategies, sometimes dominance reversal or other complications could happen, Egli cautions. “It’s not certain it will work in every single case, and people should know that.” Still, he advocates moving forward with clinical trials in people.

Researchers in the United States can do mitochondrial replacement research in the lab, but Congress has barred the U.S. Food and Drug Administration from granting permission to implant the resulting embryos in a woman’s uterus. Mitochondrial replacement therapy is legal in the United Kingdom, but researchers have not been able to apply for a license to perform the procedure while a panel of experts was reviewing the latest data, including Mitalipov’s study. In a report issued November 30 to the U.K.’s Human Fertilization and Embryology Authority, the panel recommended that mitochondrial replacement therapy could be done to prevent diseases in high risk patients. But the panel cautioned that doctors should match mitochondrial types to avoid reversion.