Fly Mitochondria Go Through Quality Control During Egg Development

During egg development in fruit flies, mitochondria (white) begin as large tubular structures (stem cell, left) containing many small rings of DNA. Then, they fragment into miniature mitochondria (cyst, right) to test the integrity of each ring. Credit: Lehmann Lab

In most organisms, 13 genes crucial to energy production reside in the mitochondria, the power plants of the cell. Now, scientists have figured out how fruit flies prevent errors from building up in those genes – a long-standing question in reproductive biology. 

Test drives aren’t just for cars. To protect the health of their offspring, fruit flies check the performance of certain mitochondria, the “power plants” of the cell.

In developing egg cells, mitochondria that don’t pass muster are culled, preventing fly larvae from inheriting corrupt mitochondrial DNA. This culling is crucial for survival, says Ruth Lehmann, a Howard Hughes Medical Institute investigator at New York University. “If mutations get passed on to eggs, they’ll accumulate over generations, and the species will eventually die out.”

Now, Lehmann’s team has figured out how the culling process actually works – how defective mitochondrial genomes are eliminated from egg cells. The discovery, reported May 15, 2019, in the journal Nature, addresses a long-standing question in reproductive biology. It could also represent a first step toward one day treating the various mitochondrial diseases that deprive cells of energy and afflict roughly 1 in 5,000 children born, Lehmann says.

Mitochondria are the structures within cells responsible for creating the energy molecule ATP. They are unique because they possess their own miniature genome – just 13 genes. Those genes are passed directly from mother to offspring through the mitochondria in eggs. Unlike the DNA within a cell’s nucleus, mitochondrial DNA doesn’t have the same mechanisms to ensure genes are copied correctly.

Scientists first realized almost a century ago that mitochondria had to have some other way to prevent DNA errors from passing to offspring, Lehmann says. “But it’s been really hard to study.” By inventing a way to label mutant DNA inside mitochondria, she and her colleagues have, for the first time, seen the culling process in action.

At the beginning of egg development (left), small rings of “good” (green) and “bad” (purple) mitochondrial DNA coexist in large, tubular mitochondria. To distinguish the good from the bad, the mitochondria fragment until they are each thought to contain, on average, a single ring of DNA (second stage). The cells then test the performance of each mini mitochondrion, degrading many of the bad ones and replicating the good (third stage). Finally, the mini mitochondria, mostly cleared of bad mitochondrial DNA, fuse back together again in the more mature egg cell (right). Credit: Thomas Hurd

Usually, each mitochondrion contains many copies of its mini genome in little rings of DNA. So when mutations occur, there’s lots of “good” DNA around to “pick up the slack,” Lehmann says. But errors do accumulate over time and, without a mechanism to catch them, they would end up in egg cells and threaten the next generation.

To discover that mechanism, Lehmann and her team, including molecular geneticist Thomas Hurd, who now leads his own team at the Universtiy of Toronto, started with flies bearing a mutated version of the mitochondrial genome – mitochondria with this mutation had trouble making ATP. Then, the team designed a way to color-code the DNA to distinguish the mutated “bad” DNA from unaltered “good” DNA. Next, they created hybrid mitochondria containing both DNA types and watched what happened.

In lab tests, they saw that the bad DNA nearly disappeared early in egg development, while the good DNA multiplied. The result suggested that egg cells were checking mitochondrial performance and culling those with defective DNA.

“Essentially, egg cells tell these little mitochondria, ‘Show me what you can do!’”

Ruth Lehmann

Lehmann’s team had a clue about how the culling happened. It occurred when the mitochondria were fragmented, their long tubular structures broken into lots of smaller pieces. Fragmentation usually occurs before cell division to help cells divvy up their mitochondria. During egg cell development, though, the scientists found that mitochondria kept fragmenting – until each contained very few or only a single ring of DNA. Those 13 genes (and the proteins they code for) then had to “stand on their own” to produce ATP, Lehmann says. They couldn’t rely on other “good” copies to compensate for them.

“Essentially, egg cells tell these little mitochondria, ‘Show me what you can do!’” Lehmann says. The mitochondria that didn’t produce enough ATP were broken down and degraded, so their corrupt DNA wasn’t inherited. The group also showed that this process somehow encouraged good mitochondrial DNA to replicate.

This mitochondrial “test drive” normally happens only in those fly cells destined to become eggs, but in the lab, the team was able to force mitochondrial fragmentation to happen in other types of fly cells – leading to culling of bad mitochondria there. The next step, she says, is to find out whether a similar process eliminates faulty mitochondria from developing egg cells in humans and other animals.