Study reveals why paternal mitochondria must be removed during early development

University of Colorado at BoulderOct 9 2024

It's one of the basic tenets of biology: We get our DNA from our mom and our dad.

But one notable exception has perplexed scientists for decades: Most animals, including humans, inherit the DNA inside their mitochondria -;the cell's energy centers – from their mothers alone, with all traces of their father's mitochondrial genome destroyed the moment sperm joins egg.

A new University of Colorado Boulder study published Oct. 4 in the journal Science Advances sheds new light on why this happens, showing that when the process fails, and paternal mitochondria slips into a developing embryo, it can lead to lasting neurological, behavioral and reproductive problems in adults.

The study, conducted in roundworms, offers new clues about what may drive some mitochondrial disorders, which hinder the body's ability to produce energy and collectively impact about one in 5,000 people. It also presents a novel approach for potentially preventing or treating them – a simple vitamin known as Vitamin K2.

These findings provide important new insights into why paternal mitochondria must be swiftly removed during early development. They also offer new hope for treatment of human diseases that may be caused when this process is compromised."

Ding Xue, senior author, professor, Department of Molecular, Cellular and Developmental Biology (MCDB), University of Colorado Boulder

When cellular batteries run low

Often described as cellular batteries, mitochondria produce adenosine triphosphate (ATP), the energy that drives virtually all cell functions.

Mitochondria have their own distinct DNA, typically passed down exclusively from the mother.

In 2016, Xue published one of the first papers to spell out just how paternal mitochondria gets wiped out – via a multi-faceted, self-destruct mechanism known as "paternal mitochondria elimination (PME)," a process documented in worms, rodents and humans alike.

"It could be humiliating for a guy to hear, but it's true," Xue joked. "Our stuff is so undesirable that evolution has designed multiple mechanisms to make sure it is cleared during reproduction."

Some have theorized that after battling it out with millions of other sperm to penetrate an egg, sperm mitochondria are exhausted and genetically damaged in ways that would be evolutionarily disastrous if passed on to future generations.

Xue and his team set out to find out what happens when paternal mitochondria do not self-destruct.

They studied C. elegans, a translucent worm which contains only 1,000 cells but develops a nervous system, gut, muscles and other tissues similar to humans.

The team was unable to completely halt PME in the worms – a testament to how resilient this evolutionary process is. But they were able to delay it by about 10 hours. When they did so in fertilized eggs, it led to significant reductions in ATP. If the worms survived at all, they had impaired cognition, altered activity and difficulty reproducing.

When the researchers treated the worms with a form of vitamin K2 known as MK-4 (best known as a bone health supplement) it restored ATP levels to normal in the embryos and improved memory, activity and reproduction in the adult worms.

Hope for little-understood diseases

The authors note that there are only a few documented cases in which paternal mitochondrial DNA might have been found in human adults. One paper describes a 28-year-old man had trouble breathing, weak muscles and could not tolerate exercise. Another documents 17 members of three unrelated multi-generational families who had fatigue, muscle pain, speech delays and neurological symptoms.

More research is needed in larger animals, but Xue suspects that in some cases, as with the worms, a mere delay in PME could be fueling hard-to-diagnose human diseases.

"If you have a problem with ATP it can impact every stage of the human life cycle," he said.

Xue imagines a day when some families with a history of mitochondrial disorders take vitamin K2 prenatally as a precautionary measure. The study, and the lab's ongoing research, could also lead to new ways to diagnose or treat mitochondrial disorders.

"There are a lot of diseases that are poorly understood. No one really knows what is going on. This research offers clues," Xue said.