Exploring mechanisms whereby Mitochondrial DNA variants remodel metabolism in humans and mice (Prof Joanna Poulton, Dr Joerg Burgstaller, Prof Karl Morten)

Supervisors

Professor Joanna Poulton

Professor Karl Morten

Dr Joerg Burgstaller - University of Veterinary Medicine Vienna

DESCRIPTION OF PROJECT 

There is an epidemic increase in diabetes worldwide, particularly in populations whose nutritional has changed substantially within a generation. This may be explained by the interaction between genotype and intrauterine nutrition (Developmental programming). The “Thrifty gene hypothesis” suggests that specific genetic adaptation to nutritional deprivation predisposes to developing type 2 diabetes when nutrition improves. In collaboration with Prof Joerg Burgstaller (Vienna) we have identified mitochondrial DNA (mtDNA) polymorphisms in human and mice lying close to mtDNA origins of replication and generating heteroplasmic length variation.  Both are candidate thrifty genes and may be involved in developmental programming (hence forth the human OriB variant and the mouse O_L variant). Furthermore, it is clear that some types of non-pathogenic mtDNA heteroplasmy can cause metabolic heart disease in mice. We hypothesize that the mtDNA variants affect the balance between pathways of mtDNA replication, the overall effect being a slower rate of mtDNA replication that can be driven by various conditions including amino acid starvation.

We plan to study human fibroblasts and mouse adult fibroblasts (MAFs) carrying these variants compared with wild type mtDNA.  We also have heteroplasmic cybrids harbouring different levels of the OriB variant.  We will use transcriptomics, proteomics and metabolomics to explore the pathways that are affected by each variant, both at baseline and under nutritional stress.  We examine mitochondrial morphology and dynamics using highthroughput image analysis. We will further develop existing methods for assessing mtDNA replication. We will compare the way that both variants remodel metabolism with the effects of nutritional stresses on the same outputs and on mtDNA.

In parallel, our Austrian collaborator Joerg Burgstaller will study how the mouse O_L variant influences the effects of maternal low protein diet on similar readouts in foetus and placenta along with weights, postnatal growth and glucose metabolism. Exploring links between the mechanisms whereby the mouse and human mtDNA variants remodel metabolism may pave the way for intervention studies in the mouse that will inform strategies to prevent human metabolic syndrome.

This project spans two multi-disciplinary, dynamic groups one based at the Nuffield Department of Women's & Reproductive Health and the other in Vienna, Austria.  Both groups have strong links to other centres locally (e.g. Novo Nordisk Research Centre Oxford, Kennedy Institute, Welcome Trust Centre for Human Genetics, the Big Data Institute and the Specialist Mitochondrial Disorders Service (NHS Highly Specialised Service) within the Oxford Genetics laboratory). Students will be strongly encouraged to publish their work, present at international conferences, attend biweekly group meetings, journal clubs, as well as departmental seminars and training courses. Above projects will be utilizing a broad spectrum of molecular biology methods including high throughput fluorescence microscopy, primary cell cultures, and flow cytometry. Additional techniques may include high-throughput sequencing (targeted, exome, whole genome, single cell transcriptomics) and Western blotting as well as immunoprecipitation.

The university also provides a wide-range of training opportunities.