Investigating how the mitochondrial respiratory chain is built and its defects that cause disease

Mitochondria are key players in health and disease. They are the main source of energy in eukaryotic cells, oxidizing sugars and fats to generate ATP through oxidative phosphorylation which is accomplished by the respiratory chain. Defects in the function of the mitochondrial respiratory chain have been associated with a group of clinical conditions defined specifically as “mitochondrial diseases” and defects in the first enzyme, Complex I, is most common. Complex I is one of the largest multisubunit membrane protein complexes known – being 1MDa and composed of 45 protein subunits. Its assembly requires the integration of both mtDNA and nuclear encoded subunits into modules that are supported by the action of a number of assembly factors. Of the 11 published assembly factors, mutations in 10 cause complex I assembly defects and disease. Using gene editing, quantitative proteomics and protein biochemistry, we have now built a more defined map of how these complex I modules are built and uncovered new, distinct roles played by a number of assembly factors (Stroud et al., 2016). Projects are available to study (1) the early steps of subunit insertion into membranes to precisely define the insertases involved; (2) the composition of assembly modules including subunits and assembly factors present; and (3) to functionally characterise 3 new assembly factors we have identified. Our aim is to address the quality control mechanisms present within mitochondria when mutations and complex I assembly dysfunction is observed in mitochondrial disease. Collaborations with clinical groups and patient material are part of this work. Projects will generate exciting new insights in this highly competitive field leading to high-impact publications. Strong mentorship is offered in a collaborative and exciting team. See www.ryanlab.org for further details. Stroud DA, Surgenor EE, Formosa LE, Reljic B, Frazier AE, Dibley MG, Osellame LD, Stait T, Beilharz TH, Thorburn DR, Salim A, Ryan MT. Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature. 2016 538(7623):123-126