In most organisms, 13 genes critical to energy production are found in mitochondria, the cell's power plants. Now scientists have understood how fruit flies prevent the accumulation of errors in these genes – a long-standing issue in reproductive biology.
Test drives are not just for cars. To protect the health of their offspring, fruit flies check the work of some mitochondria, the "power stations" of the cage.
In the development of egg cells, mitochondria are killed that do not cross the shoulder, preventing the inheritance of corrupt mitochondrial DNA. This killing is crucial to survival, "said Ruth Lehman, a researcher at New York University Medical School Howard Hughes. "If the mutations are transmitted to the eggs, they will accumulate through the generations, and the species will eventually disappear."
Now, Lehman's team has understood how the killing process actually works – how defective mitochondrial genomes are eliminated from the egg cells. The discovery, reported on May 15, 2019, in the diary natureaddresses the long-standing issue in the field of reproductive biology. This may also be a first step towards a single day to treat various mitochondrial diseases that deprive cells of energy and suffer from about 1 in 5,000 children, Lehman said.
Mitochondria are structures in the cells responsible for creating the energy molecule ATP. They are unique because they have their own miniature genome – only 13 genes. These genes are transmitted directly from the mother to the offspring via the mitochondria in the eggs. Unlike DNA in the cell nucleus, mitochondrial DNA does not have the same mechanisms to ensure that the genes are copied correctly.
Scientists first realized almost a century ago that mitochondria should have some other way to prevent the passage of DNA errors to offspring, says Lehman. "But it's really hard to study." Inventing a way to tag mutant DNA inside the mitochondria, she and her colleagues first saw the killing process in action.
Typically, each mitochondria contains many copies of its mini genome in small rings of DNA. So when mutations occur, there is a lot of "good" DNA to "get stuck," says Lehman. But mistakes accumulate over time and without a mechanism to capture them, they will end up in egg cells and threaten the next generation.
To find this mechanism, Lehman and her team, including the molecular geneticist Thomas Hurd, who now heads his own team at the University of Toronto, started with flies carrying a mutated version of the mitochondrial genome – mitochondria with this mutation had problems with ATP. The team then designed a way of coloring DNA to distinguish mutated "bad" DNA from unchanged "good" DNA. They then created hybrid mitochondria containing both types of DNA and watched what had happened.
In lab tests, they saw that bad DNA nearly disappeared at the onset of egg development until good DNA multiplied. The result shows that egg cells check the work of mitochondria and kill those with defective DNA.
"Essentially, the egg cells say to these little mitochondria," Show me what you can do! "
Lehman's team had an idea of how the killing happened. This happens when mitochondria are fragmented and their long tubular structures are broken down into much smaller pieces. Fragmentation usually occurs before cell division to help the cells separate their mitochondria. However, during egg cell development, scientists have discovered that mitochondria continue to fragment – while each contains very little or just one ring of DNA. These 13 genes (and the proteins they were coding for) had to "stay alone" to produce ATPs, says Lehman. They could not rely on other "good" copies to compensate them.
"Essentially, the ova tells these little mitochondria," Show me what you can do! "Said Leman, and mitochondria that did not produce enough ATP were destroyed and degraded so their corrupted DNA was not inherited, and the group also showed that this process has somehow encouraged good replication of mitochondrial DNA.
This mitochondrial "test drive" usually happens only on those flying cells designed to become eggs, but in the lab the team has managed to make the mitochondria fragmentation happen to other types of flies – which leads to the destruction of bad mitochondria there . The next step, she says, is to determine whether such a process eliminates defective mitochondria from egg cell development in humans and other animals.
Toby Lieber, et al., "Mitochondrial Fragmentation Causes selective removal of harmful germline mtDNA." nature, Published online on May 15, 2019 doi: 10.1038 / s41586-019-1213-4