Centre for Reproduction & Development

Mitochondrial Genetics

Lab head: Professor Justin St. John

The overall aim of our research is to understand how mitochondrial DNA (mtDNA) is replicated, transmitted and segregated so that cellular and reproductive strategies can be developed for current patients and to prevent the transmission of mutant mtDNA to subsequent generations.

Mapping mtDNA
We have mapped the patterns of replication and transmission as mtDNA passes from the fertilised oocyte into preimplantation embryos, fetuses and live offspring. Furthermore, we have studied these events following nuclear transfer and shown that donor cell mtDNA is also transmitted at highly variable levels due to the premature expression of the mtDNA specific replication factors resulting in heteroplasmy.

To provide a more focussed molecular analysis during lineage specific differentiation, we have mapped mtDNA replication events in pluripotent and differentiating embryonic stem cells, which appear to coincide with the types of ATP-generating pathway used at various stages of development.

Strategies in depleting mtDNA from donor cells
By depleting donor cell mtDNA prior to NT, we have generated live offspring that inherit their mtDNA from the oocyte only. We will apply this knowledge to karyoplast transfer to develop strategies to prevent the transmission of mutant mtDNA to subsequent generations. These strategies will also be transferable to assisted reproduction and stem cell derivation approaches.

mtDNA relationships and reprogramming
We have identified a relationship between mtDNA copy number, the steady-state levels of the catalytic subunit of the mtDNA-specific Polymerase (PolgA) and pluripotency. From this baseline, we have observed subtle differences in somatic cells reprogrammed to be ‘stem cell-like’ due to alternate patterns of mtDNA replication.

We are now progressing to derive human stem cell models of mtDNA disease to understand how mtDNA mutates and segregates. This will allow us to develop strategies to repair the genetic fault in such cells.