Mitochondrial Genetics

In eukaryotic organisms almost all genetic information is encoded in DNA present in the nucleus of the cell, but a small DNA molecule inhabits mitochondria, cellular structures that provide energy from food for the cells to use. Mitochondrial DNA contains genes that are vital for the physiological functioning of the cell. Defects that directly or indirectly affect mitochondrial genes cause human diseases. We are still do not know how mitochondrial genes work exactly. One of the ways to investigate the role of a gene, or to discover its biological function, it to change or disrupt DNA, and then to look for the effect on cultured cells, or on the whole organism. These methods of genetic modification are often powerful ways of studying disease genes encoded in the nucleus, but they cannot be applied to mammalian mitochondrial DNA. Therefore, our research goals are to identify new genes regulating mitochondria, define how these mitochondrial genes operate and to provide the technology to allow mammalian mitochondrial DNA to be modified genetically. It could be an invaluable way of understanding mitochondrial diseases and for advancing the quest for therapies.

Human mitochondria have their own genome (mtDNA) that is two hundred thousand times smaller that the nuclear genome (nDNA) and encodes only thirteen essential subunits of the oxidative phosphorylation (OXPHOS) machinery. Given the relatively small size of the mitochondrial genome our detailed understanding of the molecular mechanism that govern mitochondrial gene maintenance and expression is still surprisingly sketchy. Defects of mtDNA and nDNA are well-recognised cause of genetic disorders that have diverse clinical manifestations ranging from progressive muscle weakness to fatal infantile disease. Much of our understanding of mitochondrial molecular genetics has come from studying rare mitochondrial disorders. Currently there are no effective treatments for these diseases and there are very few animal models for them. The slow progress in gathering more data on how mitochondrial genome is regulated is, in large part, owing to our current inability to edit mtDNA. Genome engineering techniques, analogous to the ones routinely used to modify the nuclear DNA, are not in hand, so we are unable to interrogate the role of cis-acting elements for RNA expression as well as transcription or replication. Furthermore, we are still unable to introduce pathogenic mtDNA mutations at will so their effect could be studied in animal models.

In particular, the programme focuses on:

(i) Studying the basic mechanisms of mitochondrial genome regulation with the main focus on
the novel proteins responsible for nuclolytic processing of precursor mitochondrial RNA, polyadenylation of mitochondrial messenger RNA, post-transcriptional nucleotide modification of mitochondrial RNA and mitoribosome biogenesis.

(ii) The analysis of the key aspects of mitochondrial genome regulation in samples derived from patients affected with mitochondrial disease. This analysis is a source of valuable insights into the pathomechanisms of human disease, and also into basic mitochondrial molecular genetics. Importantly. They provide patients with a molecular diagnosis for prevention (prenatal genetic diagnosis) and counselling.

(iii) Developing new approaches for the genetic modification of mitochondria of living cells.
The key long-term aim is to establish routine methods of genetic modification of mammalian mitochondria. Enzymatic methods are being developed to modify the mitochondrial genome e.g. engineered zinc finger nucleases are delivered to mitochondria in order to deplete cells selectively of specific mtDNA variants.