New clues to an age-old question

8:34:00 AM

CU biologists recently shed new light on a longstanding mystery – why some of our DNA comes only from our mothers, and not from our fathers.

Fertilization is a tragic process for sperm. They fight their way to the egg, competing against one another in a race of life and death, expending massive amounts of energy along the way. When they finally reach the egg, the sperm are stripped of most of their components; everything is recycled or trashed, except for the DNA kept safely within the cell’s central compartment, the nucleus. During this process, a specialized set of DNA that’s housed in sperm’s mitochondria, the cell’s energy producer, disappears. The egg’s mitochondrial DNA, however, stays intact, which is why slightly more than half of you comes from your mom.
Now, researchers from the Molecular, Cellular and Developmental Biology and Biochemistry Departments, in collaboration with an international lab, have found new clues as to how this might happen.

Graduate student and co-first author, Hanzeng Li, walked me through what they found.

This interview has been edited for length, style and clarity.

Hanzeng Li:
This project actually started even before I joined the lab, which was in 2011. Two years beforehand, Dr. Haimin Li, another co-first author, had wanted to find out why paternal mitochondria specifically are eliminated in fertilized eggs. He thought maybe a process that gets rid of unnecessary cellular components, known as autophagy, might be how sperm get rid of big cellular structures like mitochondria.

Our lab uses a roundworm, C. elegans, as an animal model to study basic biological processes. Haimin used these animals to test several autophagy-related genes as well as more than two hundred genes thought to make mitochondrial proteins to see if these genes affected elimination of the paternal mitochondria in fertilized eggs.
He found that a gene, which makes a DNA cutting enzyme called cps-6, is involved in this process. In normal animals, DNA housed in paternal mitochondria is all gone at an early stage, but in animals that lack cps-6, this paternal DNA sticks around for a much longer time, meaning that this gene is involved in the process of disappearing the father’s mitochondrial DNA.

After Haimin found this out, Qinghua Zhou, a graduate student and another co-first author, then joined the project. Using a microscope and a dye to mark the father’s mitochondria, he followed the paternal mitochondria during fertilization and development. In animals lacking cps-6, the paternal mitochondria stay around longer than in animals that have cps-6.

To follow up on this, I examined the autophagy process that gets rid of paternal mitochondria in both normal animals and those without cps-6, and I found a difference between the two. We used super-resolution microscopy; with super-resolution power, we can see more details about the autophagosome, the cellular machinery that carries out autophagy. This is the first time the autophagosome structure has ever been seen clearly by fluorescence microscopy in C. elegans. With normal microscopy, it’s just a blur; with super-resolution microscopy we can see that the paternal mitochondria are encircled by autophagosomes.

Most of the paternal mitochondria are encapsulated by the autophagosomes in normal embryos.

After we characterized this paternal mitochondrial gene, we asked a collaborator, Dr. Byung-Ho Kang, who is an expert in electron microscopy, to get more details about what is actually defective in the process of paternal mitochondrial elimination in animals that lack cps-6. They found that compared to the maternal mitochondria which are totally healthy, the paternal mitochondria, once they get into the egg cell, make these dark aggregates; he thought the aggregates might be debris from the breakdown of the mitochondria. Without cps-6, the degradation process gets delayed.

In the final figure Qinghua, who had also determined that sperm need cps-6 and that it acts separately from the autophagy process, asked why animals need to get rid of paternal mitochondria. If we don’t get rid of paternal mitochondria, what is the outcome? This is a long-standing biological question. What would happen to the embryos if we artificially kept paternal mitochondria around for a long enough time?

This figure is complex, but the quick conclusion is that if we do not clear paternal mitochondrial, more embryos die. So far, this is the first time people have shown paternal mitochondrial elimination has a physiological relevance, at least in this model system, the C. elegans roundworm.

Hanzeng and the other researchers on this project stress that their findings are just one small part of a bigger process. There’s much more to learn about how and why paternal mitochondria are eliminated from fertilized embryos.

By Roni Dengler

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