Joanna Rorbach

Debilitating fatigue is common in patients with autoimmune, inflammatory and infectious diseases. Immune responses require massive amounts of energy and mitochondria are responsible for generation of ATP from oxidation of nutrients. This organelle also activates immune cells via the release of nucleic acids, phospholipids, metabolites and reactive oxygen species. Release of such signals is essential for killing pathogens but when produced in excess can also drive chronic inflammatory responses. The central role of mitochondria in regulating immune responses forms the basis for a new hypothesis where mitochondrial sensitivity towards stressors associated with modern life (e.g. obesity, pollutants) is a missing link explaining the increased prevalence of immunological diseases. However, this hypothesis lacks mechanistic evidence. This project aims to improve current understanding of the structure, biophysical properties and functional regulation of mitochondria in human immune cells, as well as the delicate balance between energy production, life-saving protection from pathogens and devastating inflammatory disease. A new research field will be created where multidiciplinary studies of mitochondrial structure (Testa), biophysical properties (Sezgin) and function (Rorbach) are integrated into studies of human cells, from individuals with/without immune disease (Brodin), which together hold promise for development of new and combined technologies, not usually considered together.

Mitochondria produce most of the energy the body acquires through food, and are thus pivotal players in cellular metabolism. Central to mitochondrial biology is the DNA in the organelle (mtDNA): its maintenance, correct RNA processing, and efficient translation are all essential and must be coordinated to ensure proper mitochondrial function and cellular physiology. Defective maintenance or expression of mtDNA alters energy and nutrient metabolism, which are increasingly recognized to impact medical disciplines, ranging from hundreds of genetic disorders to neurodegeneration, immunology, transmissible disease, cancer and ageing. A deep understanding of the mitochondrial gene expression system and new methods are urgently needed to develop treatments for the full panoply of mitochondrial disorders that feature mtDNA perturbation. MITGEST will unite world-class academic excellence in mtDNA maintenance and expression with private sector expertise in nucleic acid chemistry and the development of mitochondrial therapeutics to address this urgent need. As the first research training programme in this field to take a fully integrated approach, our 10 doctoral candidates (DC) will elucidate how mtDNA is maintained and expressed and support the development of new methods to analyse RNA and DNA metabolism in mitochondria. These advances will complement and facilitate/enhance innovative treatment strategies and experimental medicine studies designed to mitigate mitochondrial dysfunction in a range of human diseases. Our network of 7 beneficiaries and 12 associated partners from 8 European countries and Israel builds on proven collaborations and establishes new partnerships to deliver intersectoral and multidisciplinary scientific and transferable skills training to our 11 PhD students to generate the next generation of highly-skilled scientists able to exploit the latest advances in mitochondrial biology and medicine.