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How and why mitochondrial DNA is inherited from only one parent

Secondary Supervisor(s): Dr Felix Chan

University of Registration: University of Birmingham

BBSRC Research Themes:

• Understanding the Rules of Life (Stem Cells)

Project Outline

Inside our cells, DNA resides in two places 鈥� the nucleus and the mitochondrion. The nuclear DNA encodes the organism鈥檚 blueprint, while mitochondrial DNA (mtDNA) mainly encodes proteins required for energy production. Unlike nuclear DNA, which is derived 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 a forward genetic screen in Drosophila, we identified proteins involved in eliminating paternal mtDNA during spermatogenesis. This project will employ genetic and biochemical approaches to characterise these proteins and reveal how they regulate paternal mtDNA removal during sperm development. It will help us build a full picture of the mechanisms governing maternal inheritance and contribute to the understanding of sperm development and mtDNA evolution.

Decoding Mito-Nuclear Interactions in Mitochondrial Disease

Secondary Supervisor(s): Dr Yun Fan

University of Registration: University of Birmingham

BBSRC Research Themes:

• Integrated Understanding of Health (Ageing, Diet and Health)

Project Outline

Mitochondrial DNA (mtDNA) may be small, but its influence on human health is profound. Over 350 pathogenic mtDNA mutations have been linked to a diverse array of mitochondrial disorders, which collectively affect 1 in 5,000 individuals. Yet, the clinical outcomes of these mutations are highly unpredictable鈥攊ndividuals with the same mtDNA mutation can experience dramatically different symptoms, or none at all. This striking variability points to a critical but poorly understood genetic interaction: the crosstalk between nuclear and mitochondrial genomes.

Because proper mitochondrial function depends on coordinated expression between these two genomes, variation in nuclear DNA may explain why some mtDNA mutations are more harmful in certain individuals. However, the precise mechanisms by which nuclear polymorphisms modulate mitochondrial disease severity remain largely unknown.

This project harnesses powerful genetic tools in Drosophila to dissect these mito-nuclear interactions. Using mtDNA mutants with impaired complex IV activity, we have uncovered striking cases where nuclear genetic variation rescues mtDNA dysfunctions 鈥� restoring energy production, lifespan, and mobility. We've already mapped several nuclear polymorphisms responsible for this rescue in specific genetic backgrounds. The core aim of this project is to investigate the cellular and biochemical mechanisms behind this rescue effect. Time permitting, the student will also explore tissue-specific mito-nuclear interactions using mtDNA mutants that exhibit male-specific infertility.

By identifying nuclear factors that buffer the effects of pathogenic mtDNA mutations, we can uncover new therapeutic targets and strategies for treating mitochondrial diseases. Moreover, as mitochondrial replacement therapies鈥攕uch as 鈥渢hree-parent babies鈥濃�攂ecome more common, understanding the compatibility between nuclear and mitochondrial genomes becomes not just important, but urgent.