Talk Title:

mtDNA: the Cinderella of cancer genetics

Abstract:

Mutation of mitochondrial DNA (mtDNA) can have broad impacts on cell metabolism and organism physiology, and mutation of mtDNA is among the most common somatic alterations to the tumour genome.

Mutation of mtDNA is an established cause of multiple hereditary metabolic diseases, with metabolic impacts on patient tissues that bear more than a passing resemblance to typical cancer metabolic phenotypes such as the Warburg effect. However, mutation of mtDNA remains something of an outlier in the genomics of disease for a number of reasons. Chief among these are: the highly compact nature of the genome (37 genes and all necessary regulatory sequences contained within 16kb), the functional unity of gene products (all are required for an intact mitochondrial respiratory chain, required for energy metabolism and mitochondrial function) and the multi-copy nature of mtDNA, with 100’s to 1000’s of copies of the genome per cell situated within the mitochondria and separated from the chromosomes in the nucleus.

In particular, this multi-copy status means that mutations of mtDNA are typically found as a mixture with wild-type copies, a state known as heteroplasmy. In germline mitochondrial disease, a threshold effect is often observed where >70-80% of the total mtDNA pool is necessary for clinical phenotypes to manifest, and germline mutations of mtDNA are therefore thought of as being functionally recessive.

In collaboration with the Reznik lab we published the most comprehensive pan cancer analysis of mtDNA variation to date, establishing clear evidence of selective pressures on the mtDNA mutational landscape and a obvious influence on tumour gene expression. More recently, we have engineered recurrent mutant alleles identified in patients into the mitochondrial genome of mouse models of melanoma, demonstrating that these mutations modify cell metabolism and tumour biology, generating an inflammatory state also observed in patients and with clinically relevant impacts e.g. response to checkpoint blockade.

My lab now focuses on determining the impact of mtDNA mutations in other cancer types beyond melanoma and engineering metabolic states to mimic the pro-inflammatory, treatment primed tumour microenvironment of mtDNA mutant disease.