Genetic disorders affecting mitochondrial oxidative phosphorylation (OXPHOS) constitute the most common form of inherited metabolic disease, affecting ~1/5000 births. There are few, if any proven treatments and the diagnosis rate is only ~60%. Those lucky enough to receive a molecular diagnosis often wait months or years. We are developing the use of computational proteomics to complement existing diagnostic strategies1, discover new disease genes2, and understand the impact of mitochondrial dysfunction on a systems-wide level3.
In this talk I will provide an update on our project to generate CRISPR/Cas9 knockouts of every known OXPHOS subunit and assembly factor – in total this represents >120 nuclear encoded genes. We profile the changes in the global proteome of each knockout cell line, using the results to both improve our understanding of how the cell responds to mitochondrial dysfunction in patients and understand the specific molecular function of novel candidate disease genes. Complementary to this, I will present our latest proteomic profiling data from patients with mitochondrial disease, demonstrating how the datasets can work together to improve our understanding of mitochondrial function and dysfunction in health and disease.