Every time a sperm fertilises an egg, the father’s mitochondrial DNA is actively destroyed, leaving only the mother’s copy to be inherited. Why this happens so consistently across the animal kingdom—and what goes wrong when it doesn’t—remains largely unknown. This project uses fruit flies to answer both questions. The researchers have already identified the proteins that eliminate paternal mitochondrial DNA during sperm development, and they have created mutant flies that can pass on both parents’ mitochondrial DNA. The first part of the work will map exactly how those proteins remove the paternal DNA. The second part will let the mutant flies evolve in the lab, testing two long-standing theories: that uniparental inheritance prevents harmful mitochondrial mutations from spreading through a species, and that mixing two mitochondrial genotypes harms an organism’s health. This is fundamental science—it will not produce a therapy or a product tomorrow. But understanding a core principle of inheritance could eventually inform fertility treatments (around 7% of men have fertility issues linked to sperm development) and offer a simpler alternative to mitochondrial replacement therapy, the “three-parent baby” technique, by allowing natural paternal leakage of healthy mitochondrial DNA.
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Inside our cells, DNA resides in two places - the nucleus and the mitochondrion. The nuclear DNA encodes the organism's blueprint, while mitochondrial DNA (mtDNA) mainly encodes proteins required for energy production. Unlike nuclear DNA, which is derived half from each parent when an egg is fertilised by a sperm, mtDNA is inherited solely from the mother, through the egg. In various species including humans, a fascinating phenomenon occurs during sperm development, where paternal mtDNA is eliminated to ensure only maternal mtDNA is passed on. However, how and why maternal inheritance of mtDNA occurs so consistently across the animal kingdom remains largely unexplored. Through our previous research involving fruit flies, a model organism carrying mtDNA like that of humans, we identified proteins involved in eliminating paternal mtDNA during sperm development. Moreover, we isolated mutant flies capable of transmitting paternal mtDNA to progeny. This project will build on these findings to uncover how and why mtDNA is inherited from only one parent. There are two parts to the project. The first part employs genetic and biochemical approaches to characterise the various proteins identified in our earlier work to reveal how they regulate paternal mtDNA removal during sperm development. This part will help us build a full picture of the mechanisms governing maternal inheritance. The second part involves laboratory evolution experiments using our mutant flies that allow transmission of paternal mtDNA. This part will uncover how violating uniparental inheritance of mtDNA impacts the fitness of individual organisms and overall populations. Our work has broad potential applications in the fields of biology, evolution, and biomedical research. At its core, delving into the mechanisms governing the uniparental inheritance of mtDNA provides molecular insights into this fundamental biological principle that operates across many species. This project extends beyond just understanding how mtDNA is passed down; it investigates what happens if offspring inherit mtDNA from both parents. There are two popular theories about why mtDNA is only inherited from mothers: 1) it limits harmful/selfish mtDNA to certain female groups, thus preventing it from catastrophic spreading at the species level; and 2) it prevents organisms from containing more than one mtDNA genotype as that could cause health problems. Using our special mutant flies that allow paternal mtDNA transmission, we can finally test these ideas in the lab and explore the importance of mtDNA uniparental inheritance for the evolution of life. Our work could also lead to biomedical applications. Compared to mitochondria replacement therapy (i.e. three-parent babies technique), which requires healthy female donors and complicated in vitro fertilisation procedures, paternal leakage could offer a more straightforward and natural way to pass on functional mtDNA to offspring when the mothers carry harmful mtDNA mutations. In addition, our research contributes to the understanding of sperm development, which could help to address issues related to male fertility that affect ~7% of the human male population. In conclusion, this curiosity-driven project will deliver new knowledge about a key biological principle fundamental to all eukaryotic life from molecular to populational levels. It strongly aligns with BBSRC's commitment to advancing the fundamental understanding of living systems and an integrated understanding of health, and driving impactful innovations in bioscience research.
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