Research interests
mtDNA: With few exceptions, animal mtDNA is a circular dsDNA molecule, encoding 13 proteins for oxidative phosphorylation. Mutations on mtDNA have been linked to a variety of mitochondrial diseases, affecting 1 in 5,000 people in the UK.
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mtDNA encodes <1% of mitochondrial proteins, with the rest being encoded by the nuclear genome. Therefore, mtDNA maintenance and mitochondrial function rely heavily on the co-existing nuclear genome.
Mitochondrial genetics: The genetics of mtDNA is different from the nuclear genome in almost every aspect: 1) mtDNA follows a strict uniparental inheritance (often from the mother); 2) The presence of many copies means two or more genotypes can be present in a single cell/organism (i.e. heteroplasmy); Most disease-causing mtDNA mutants co-exist with wild type mtDNA, and only become pathogenic when their levels exceed a certain threshold. 3) mtDNA follows relaxed replication and random segregation when the cell divides; and 4) Recombination is rare.
As mtDNA molecules replicate at random and lack mechanisms that ensure unbiased segregation when the cell divides, selection can easily bias transmission of one genome over another to alter the level of a mtDNA mutant during an individual’s lifetime and from mother to offspring. This leads to complex transmission patterns that shape the progression of mtDNA linked disorders and the evolution of mtDNA. In addition to disorders caused by accumulation of a particular mutant, random mtDNA mutations have been shown to increase with age, contributing to mitochondrial dysfunction and various age-related conditions.
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Our vision: We are interested in understanding the molecular mechanisms that govern heteroplasmy transmission during development and ageing. In particular, we want to know why a mutant mitochondrial genome increases in abundance to cause diseases in some cases while in others it is eliminated. By creating fruit flies carrying both functional and pathogenic mitochondrial genomes, we perform systematic and detailed studies to identify nuclear factors and mtDNA sequence polymorphisms that bias the transmission of one genome over the other.
We are also interested in understanding how repair mechanisms
maintain mtDNA integrity during development, how maternal inheritance of mtDNA is guaranteed, how complex mito-nuclear interactions modulate the pathogenic expression of mtDNA mutations and how mitochondrial dynamic impacts development. These studies provide insights into genome evolution, ageing and human diseases.
