(i) Scientific basis: Diabetes can lead to increased risk of severe complications, including heart and kidney disease, nerve damage and blindness. Diabetic complications currently account for >10% of the UK NHS budget, are a pressing global health concern, and understanding the molecular mechanisms behind them is of paramount importance. Mitochondrial pathways play a pivotal role in this risk, as high glucose levels in diabetes trigger mitochondrial dysfunction, causing oxidative stress, impaired ATP production, and the release of reactive oxygen species (ROS), leading to cellular inflammation, apoptosis, and disrupted metabolism. Despite this, the precise causal pathways to mitochondrial dysfunction are not well understood, making these processes hard to target therapeutically.
(ii) Aims:
1) Identify genetic variation that influences the likelihood of individuals with diabetes developing serious secondary complications using population level genetics.
2) Identify potential causal mechanisms of complications by tracking the timeline of molecular events that lead to mitochondrial dysfunction in cell models.
3) Test a range of protective compounds in cell models to ameliorate mitochondrial dysfunction and thus protect from downstream disease.
(iii) Techniques and skills: The student will receive training in interdisciplinary skills including computational analysis of genetic data (with Dr. Hodgkinson, Guy’s Tower), mitochondrial targeted Nanopore sequencing (both supervisors), cell/molecular biology techniques including mammalian cell culture, mitochondrial function/cellular health analysis (with Dr. Malik, Hodgkin building, Guys campus).
(iv) Objectives for each year:
Year 1: Screen large population-based cohorts to identify diabetes patients with none and >1 complication. Develop computational strategies for screening for variants in datasets from nuclear and mitochondrial genomes. Set up cell model systems for 2 selected complications.
Year 2. Design and implement time series experiments in relevant cell models to survey changes in mitochondria (mt) DNA variation, mtDNA copy number, mtRNA profiles and mitochondrial functional assays after exposure to high glucose and lipids.
Year 3: To test drug compounds that protect the cell against the changes observed in cell models (above), and therefore protect against mitochondrial damage.
This is a multidisciplinary project which will provide excellent training for the student in cutting edge techniques an exciting area and will generate data with strong translational potential .
The role of mitochondrial dysfunction in diabetic complications and potential therapies
Representative Publications
• “Altered Mitochondrial Function, Mitochondrial DNA and Reduced Metabolic Flexibility in Patients With Diabetic Nephropathy” Czajka et al., (2015) Ebiomedicine. DOI: 10.1016/j.ebiom.2015.04.002 • “A Diet Induced Maladaptive Increase in Hepatic Mitochondrial DNA Precedes OXPHOS Defects and May Contribute to Non-Alcoholic Fatty Liver Disease” Malik et al., 2019. Cells. doi: 10.3390/cells8101222 • Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits. Kraja et al., 2019 doi: 10.1016/j.ajhg.2018.12.001.
• “Nuclear Genetic Regulation of the Human Mitochondrial Transcriptome “ Ali, A.T., et al., 2019.eLife. DOI: 10.7554/eLife.41927 • “Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease “ Fairbrother-Browne et al., 2021, Communications Biology 4: 1262.DOI: 10.1038/s42003-021-02792-w • “Highly accurate quantification of allelic gene expression for population and disease genetics” Ali et al., 2021. Genome Research. doi: 10.1038/s42003-021-02792-w