Systems approaches to understanding the assembly of mitochondrial machines

  • Stroud, David, (Primary Chief Investigator (PCI))
  • Ryan, Mike (Chief Investigator (CI))

Project: Research

Project Description

Human mitochondria are important for many aspects of cellular function, however their core role is undoubtedly generation of ATP through oxidative phosphorylation (OXPHOS) which occurs on the 5 membrane protein complexes of the respiratory chain. Disorders of OXPHOS are the most common inherited metabolic disorders, affecting 1/5000 births. Mutations in >180 nuclear genes affect the 5 OXPHOS complexes and cause mitochondrial disease. Diagnostic approaches typically focus on known mitochondrial genes, whereas the genetic complexity of the disease means drugs targeting one OXPHOS system often fail when another is defective. Functionalisation of the mitochondrial proteome is therefore crucial for improving diagnostic and treatment outcomes. We have developed an innovative systems-biology approach that couples gene-editing and quantitative proteomics with biochemical and cell biology techniques to provide new and functional insights into the assembly of mitochondrial complexes. Here we propose to use these tools to study human OXPHOS complexes II, III, IV & V. We will determine the importance of every nuclear encoded subunit in these complexes, identify novel structural modules and associate them with existing and new assembly factors that we will characterise. Assembly pathways for each complex will be re-defined, and our results will be used in future diagnostic screens and for therapeutic design.
StatusActive
Effective start/end date1/01/1831/12/20