Proteomics and mitochondrial disease

Abstract

Disorders of mitochondrial oxidative phosphorylation (OXPHOS) present with almost any symptom, at any age with any mode of inheritance. OXPHOS disorders are the most common group of inherited metabolic diseases and occur in ~1/5000 births. There is no ‘gold standard’ diagnostic test and most paediatric diagnoses rely on finding an enzyme defect while molecular investigations are typically restricted to testing for common mutations or sequencing of specific candidate genes. While next generation sequencing (NGS) approaches have yielded great insights into the identification of pathogenic mutations, these generally focus on sequencing of known mitochondrial and disease related genes, yielding a molecular diagnosis in ~60% of cases. Recent advances in proteomics have improved such that much of the human cellular proteome can now be determined in a matter of hours. In addition, with the use of quantitaive approaches including stable isotope labeling of cells in culture (SILAC), differences between the proteomes of diseased and controls cells can be measured. We are now investigating the use of quantitative proteomics as a complementery tool to NGS in the molecular diagnosis of OXPHOS disease, and to ultimately identify novel candidate genes that cause disease.