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Why Evolution Erased Dad’s Mitochondria

A mitochondria.
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We get our energy from our mothers, and a recent study from the University of Colorado Boulder (CU Boulder) may have uncovered the exact reason behind this. The research, published in Science Advances, describes what happens when paternal mitochondria infiltrate the developing embryo.

The self-destructive mechanism of paternal mitochondria elimination (PME)

Mitochondria are essential organelles that produce the energy needed for nearly all cellular functions. They generate adenosine triphosphate (ATP), the molecule that serves as the primary energy currency of the cell. These tiny structures carry their own DNA, which is almost always inherited solely from the mother. The reason why all traces of the father’s mitochondrial genome are eliminated during fertilization has puzzled scientists for years.


PME takes place shortly after the sperm joins the egg. The process was first described by senior author Dr. Ding Xue, a professor in the department of molecular, cellular and developmental biology at CU Boulder, in a study in 2016.

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

 

The highly efficient self-destruct mechanism has been documented in worms, rodents and humans. Many researchers have suggested that after competing with millions of other sperm to reach and penetrate the egg, the mitochondria within sperm cells become exhausted and sustain genetic damage, which could be evolutionarily harmful if transmitted to future generations.

 

But what happens when this process fails?

Delaying PME results in impaired physiological function

Xue and the team studied PME in Caenorhabditis elegans (C. elegans), a translucent roundworm, to gain insight into this elusive mechanism. C. elegans only have 1,000 cells, yet they still develop a nervous system, gut, muscles and other tissues like humans.

 

During fertilization, the paternal mitochondria lose their inner membrane integrity, and the mitochondrial DNA is broken down by endonucleases. To understand what would happen if PME didn’t occur, the team set out to stop this process.

 

Although unable to completely halt PME in worms, the team was able to delay it by ~10 hours. The resulting fertilized eggs had significant reductions in ATP production, which led to increased embryonic lethality and long-term physiological defects. In the few worms that survived, impaired cognition, altered activity and difficulty reproducing were observed.

 

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

Treating ATP reduction with vitamin K2

Xue and the team treated the PME-delayed animals with MK-4, a subtype of vitamin K2 that can improve mitochondrial ATP production.

 

MK-4 restored ATP levels in the early embryos and rescued the physiological defects of the adult animals, suggesting a possible therapeutic pathway for PME-related issues and mitochondrial diseases.

Addressing hard-to-diagnose human disease

“These findings provide important new insights into why paternal mitochondria must be swiftly removed during early development,” said Xue.

 

“They also offer new hope for treatment of human diseases that may be caused when this process is compromised,” he added.

 

Although further investigations are needed in larger animals, the study suggests even a short delay in PME could result in hard-to-diagnose human diseases.

 

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

 

There are a limited number of documented cases in which paternal mitochondrial DNA has been identified in human adults. In one, a 28-year-old man presented with issues including trouble breathing, weak muscles and an inability to tolerate exercise.

 

The team believes vitamin MK-4 could become a promising treatment option for not only mitochondrial diseases but also PME-related symptoms and diseases.

 

Reference: Zhang H, Zhu Y, Xue D. Moderate embryonic delay of paternal mitochondrial elimination impairs mating and cognition and alters behaviors of adult animals. Sci Adv. 2024. doi: 10.1126/sciadv.adp8351


This article is a rework of a press release issued by the University of Colorado Boulder. Material has been edited for length and content.