Mitochondrial ‘mother’s curse’ cuts male fly fertility

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There is new evidence that the “mother’s curse”—the possibility that moms may transmit genes to their children that harm their sons but not their daughters—holds true in animals.

Such a possibility arises because there are two independent parts of the genome in the eukaryote cells, which are found in plants and animals, and the two are locked in a “conflict-driven molecular arms race” that impacts human health and wellness. The lion’s share of the genome is located in the cell nucleus. But there is also a much smaller secondary portion located in the mitochondria.

According to the generally accepted theory, mitochondria were originally independent bacteria that developed an ability to tap highly toxic oxygen molecules as a powerful energy source. Eukaryotes lacked this capability, so some of them found a way to swallow the mitochondria’s ancestor without digesting it—converting it into an “endosymbiont,” an organism that lives within the body of another organism.

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Unlike the nuclear genome, which is built from a combination of father’s and mother’s genetic material, the mitochondrial genome is passed down exclusively from the mother. As a result, male offspring are an evolutionary dead end. While natural selection actively suppresses mutations in the mitochondrial DNA (mtDNA) that weaken females, there is no direct mechanism for weeding out those that weaken males: a situation that leads to the mother’s curse.


Males but not females


“We weren’t looking specifically for mutants that affect fertility, but, in retrospect, it makes sense.”

“In the 20 years since this possibility was recognized, a few mitochondrial mutants have been reported that have deleterious effects on male offspring,” says Maulik Patel, assistant professor of biological sciences at Vanderbilt who headed the study, “but none of them convincingly showed that the mutants did not have any negative effects on the females.


The discovery appears in the journal eLife.

The ‘Red Queen hypothesis’

The “mother’s curse” is one of the more bizarre consequences of natural selection. According to evolutionary theory, the mitochondrial DNA (mtDNA) and nuclear DNA are locked in an unending competition. As one accumulates beneficial mutations, then the other is forced to adapt. This is known as the “Red Queen hypothesis.” The name is derived from a statement made by the Red Queen in Lewis Carroll’s Through the Looking-Glass: “…it takes all the running you can do, to keep in the same place.”

In plants, which have much larger mitochondrial genomes that contain a larger number of genes, striking instances of male-harming mitochondria have already been discovered. The mitochondrial genome in animals is much smaller, however, making it much harder to detect similar male-harming mutations.


“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,” says Patel. Miriyala and Littleton were research technicians at the Hutchinson Center.


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“We weren’t looking specifically for mutants that affect fertility,” says 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.”

Male sterility


The researchers also discovered that the mutant enzyme was temperature sensitive. Turning up the temperature in their cages by four degrees Celsius caused the male carriers to become almost completely sterile. This allowed the scientists to perform an additional experiment to test a second prediction of the mother’s curse hypothesis: that the nuclear genome should evolve mechanisms for restoring male fitness by suppressing the activity of male-harming mtDNA mutants.

They mated females with the mutant mtDNA with males from a number of different fruit fly strains collected from a number of different locations around the world. Then they assayed the male offspring’s fertility and were surprised to discover that the nuclear genomes from many of the strains were capable of completely restoring the males’ fertility.

“The strategy that we used in this study, combined with advances in methods for manipulating mitochondrial genomes, provides us with exciting new opportunities to explore the ‘dark side’ of one of the oldest and most important symbioses on the planet. 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,” says Patel.

In addition to Patel, Miriyala, and Littleton, coauthors of paper are from the Fred Hutchinson Cancer Research Center, the University of Michigan, and the University of Washington. The research took place in the laboratory of evolutionary biologist Harmit Singh Malik at the Fred Hutchinson Cancer Research Center.

The Hay Whitney Foundation, the Mathers Foundation, and National Institute of Health supported the work.

Source: Vanderbilt University