Molecular mechanisms of tissue specificity in mitochondrial disease
Mitochondrial diseases are genetic disorders that impair the energy production in our cells and affect about 1 in 5,000 people in the UK. Production of energy is crucial for normal functioning of all cells and organisms. Nevertheless, symptoms of mitochondrial disease can be very diverse and tissue-specific and often only appear in adult life. This suggests that some tissues and stages of life are relatively protected from mitochondrial dysfunction, while others are more susceptible.
In the lab, we study how cells and tissues respond to mitochondrial dysfunction. The brain is the main focus of our research as it is frequently affected by mitochondrial disease, with a major impact on disability and death. Our overall aim is to identify novel determinants of tissue-specific phenotypes of mitochondrial and neurodegenerative diseases, and to uncover potential therapeutic targets to treat these disorders.
The main research themes are (1) how cell-type composition of a tissue and cell-to-cell communication may provide protection against mitochondrial disease, and (2) how transcription of the nuclear genome is regulated when a cell is confronted with mitochondrial dysfunction.
We use a wide range of approaches, but our favourite model system is the fruit fly, Drosophila melanogaster. Up to 70% of all human disease genes also have orthologs in Drosophila, and thanks to its powerful genetics, Drosophila is widely used as a model to study development and human disease. We employ advanced genetic tools and combine these with confocal and super-resolution imaging, biosensors, and innovative DamID-based sequencing approaches to study the autonomous and non-cell-autonomous effects of tissue- and cell-type specific mitochondrial dysfunction in vivo, in the developing and aging brain.
Ultimately, we hope to uncover potential therapeutic targets to treat mitochondrial and neurodegenerative disorders. This will provide novel insight for other conditions where mitochondrial dysfunction plays a role too, including diabetes and cancer.