Sex-specific genetic activity identified in copepod mitochondria

“We found a pronounced 'men are from Mars, women are from Venus' pattern,” says marine and environmental biologist Suzanne Edmands.

It does not refer to human psychology, but rather to mitochondria, the cellular components responsible for energy generation.

Edmands, a professor of biological sciences in the USC Dornsife College of Letters, Arts and Sciences, recently published research in the Proceedings of the National Academy of Sciences this reveals vast differences in gene activity in the mitochondria of men compared to women.

Although the study focused on tiny marine organisms called copepods, Edmands says the results have serious implications for human medicine. “The mitochondrial genome of these animals looks very similar to ours: same genes, same functions and similar genome size.”

Hundreds of human diseases are linked to dysfunctional mitochondria, affecting muscles, organs such as the liver and pancreas, the brain and even the eyes and ears. Examples include muscular dystrophy, diabetes, and Alzheimer's disease.

Current treatments for these diseases are largely the same for men and women, but Edmands believes his study indicates that this approach is often flawed. “Our results highlight the need to develop sex-specific mitochondrial therapies.”

Mitochondria behave differently in men and women

Scientists believe that mitochondria originated in a single-celled organism that was swallowed up by another about 1.5 billion years ago. Over time, these submerged organisms evolved to specialize in producing energy for their host cells. This symbiotic relationship proved so beneficial that it persisted throughout evolution.

This ancient mixture of two organisms explains why mitochondria have their own genome, distinct from the cell's nucleus.

It has already been established that gene activity within mitochondria varies depending on the sex of the organism. “Mitochondrial function may differ between men and women, who typically have different energy needs and tradeoffs,” says Edmands.

But Edmands wanted to know more about these sex differences. His study aimed to identify which mitochondrial genes are most active in men and which are most active in women, as well as how these genes interact with nuclear genes in both sexes.

To ensure she was observing sex differences caused by mitochondria, she studied a species of copepod that lacked sex chromosomes.

Sex chromosomes also cause differences between females and males, and these sex chromosome effects are difficult to distinguish from sex-specific mitochondrial effects.

Mitochondria study reveals major gender differences

Edmands' group is the first to test the effects of 37 genes in the mitochondrial genome – genes that copepods and humans share.

She found that men demonstrate more activity on all mitochondrial protein-coding genes than women. Males also show higher expression of nuclear and mitochondrial genes that interact with each other to affect cell energy metabolism.

Females, on the other hand, show higher expression of genes related specifically to the production and maintenance of mitochondria.

Why are these differences significant? Although mitochondria contain only a tiny fraction of the DNA found in the nucleus, the study showed that mitochondrial genes affected processes in all 12 chromosomes in the nucleus, exerting an overall influence.

Additionally, the mitochondrial and nuclear genes that interacted were almost completely different between the sexes.

Tips for Mitochondrial Diseases

Edmands says the findings can help inform treatment approaches for mitochondrial diseases in humans, particularly mitochondrial replacement therapy. This technique involves replacing defective mitochondria from a mother's egg with healthy mitochondria from a donor.

“Our results show that swapping a different mitochondrial type is not like changing a battery,” she says. “Disparities between donor mitochondria and nuclear DNA can have sex-specific implications throughout the genome.”

Understanding which nuclear and mitochondrial genes interact, as well as the differences in these interactions between men and women, could help clinicians select the right type of mitochondria to ensure greater success with these therapies.

More mitochondrial work to come

In future studies, Edmands hopes to use additional methods to study sex-specific differences in mitochondrial function. She thinks her study design, which avoids sex chromosomes, could also inspire other scientists to engage in similar research.

“I think scientists will find this to be a particularly compelling demonstration of sex-specific mitochondrial effects on gene expression, because it is not confounded with sex chromosome effects,” she said.

Reference: Li N, Flanagan BA, Edmands S. The role of mitochondria in sex- and age-specific gene expression in a species lacking sex chromosomes. Proc Natl Acad Sci. 2024;121(24):e2321267121. doi: 10.1073/pnas.2321267121

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