Unlike the nuclear genetic material that comes from both our father and mother, the mitochondrial genome is inherited exclusively from our mother. Researchers at the Fred Hutchinson Cancer Research Center have shown for the first time that this may lead to mutations in the mitochondrial DNA (mtDNA) that are harmful to a women’s sons but not to their daughters, a phenomenon known as “mother’s curse.”
The study, “A mitochondrial DNA hypomorph of cytochrome oxidase specifically impairs male fertility in Drosophila melanogaster,” published in eLife, describes a mutation in mtDNA that decreases the fertility of male fruit flies but does not affect females.
“In the 20 years since this possibility was recognized, a few mitochondrial mutants have been reported that have deleterious effects on male offspring,” Maulik Patel, an assistant professor of biological sciences at Vanderbilt who headed the study, said in a press release, “but none of them convincingly showed that the mutants did not have any negative effects on the females.”
Since only women can pass their mitochondrial genetic material to offspring, natural selection is actively eliminating mtDNA mutations that weaken females. Those with deleterious mutations are less likely to reproduce and transmit their genetic material. But since there is no selective pressure over the mtDNA of male offspring, there is no mechanism that suppresses such harmful mutations.
To test this long-existing hypothesis, the researchers created 18 independent lines of fruit flies, each composed of 300 females and 100 males. In 12 of these lines, virgin females were collected during 35 generations and mated with males from the original stock. In the remaining six lines, females were allowed to mate with sibling males of their choice.
“Ganesh Miriyala, Aimee Littleton, and I spent a year and a half ‘flipping flies’ with no idea of whether we would end up with anything meaningful,” Patel said.
During this time, the researchers were monitoring the males in each generation and assessing their fitness. In the end, they found a point mutation in the mtDNA that modified a subunit in the cytochrome C oxidase enzyme. This mutation was found to reduce sperm production and motility prematurely as the males aged, which markedly affected their fertility. But the mutation did not have any effect on females.
“We weren’t looking specifically for mutants that affect fertility,” said Patel, “but in retrospect, it makes sense. Mutants that affect males but not females must be affecting tissues that are different in males and females.”
According to an evolutionary theory, the mtDNA and nuclear DNA are constantly competing. When one accumulates beneficial or harmful mutations, the other adapts.
Researchers took advantage of the fact that the mutant cytochrome C oxidase was temperature sensitive to test this hypothesis. They predicted that the nuclear genome would develop mechanisms to suppress the harmful mtDNA mutation and restore male fertility.
Indeed, when they mated females with the mutant mtDNA with males collected from a number of locations around the world, many of the strains were found to have completely restored male fertility.
“We hope this will lead to ways to treat mitochondrial diseases, only a few which currently can be treated, and which are inherited by one newborn in every 200 and become manifest in about one adult out of 5,000,” Patel said.