Diverse genes involved in distinct mitochondrial processes cause disease

Mitochondrial Disease

Defects in oxidative phosphorylation (OXPHOS) result in human mitochondrial disease and affect ~1/5,000 live births. Onset can be at any age, but severe childhood disease is common and symptoms regularly involve neurological and muscular disease. Defects in respiratory chain Complex I is the most common mitochondrial disease, and results in multi-system disorders. Complex I contains 44 different protein subunits, with 7 subunits encoded by mitochondrial genes and the rest by nuclear genes. Complex I failure leads to defects in aerobic respiration with elevated lactic acid and ketone bodies. Complex I is also known to generate reactive oxygen species, an important contributor to many mitochondrial pathologies.

In collaboration with the Murdoch Childrens Research Institute at the Royal Children's Hospital, we analyse cells from patients for defects in assembly of the respiratory chain, in particular Complex I. We complement our patient studies by making knockouts in cell lines (using CRISPR/Cas9) and performing cellular, biochemical and proteomic approaches to understand the function of specific genes involved in OXPHOS

 

  Mitochondrial oxidative phosphorylation and protein complexes

Recent publications:

Stroud DA, Maher MJ, Lindau C, Vögtle FN, Frazier AE, Surgenor E, Mountford H, Singh AP, Bonas M, Oeljeklaus S, Warscheid B, Meisinger C, Thorburn DR, Ryan MT. COA6 is a mitochondrial complex IV assembly factor critical for biogenesis of mtDNA-encoded COX2. Hum Mol Genet. (2015) 24(19):5404-15. Pubmed

Formosa LE, Mimaki M, Frazier AE, McKenzie M, Stait TL, Thorburn DR, Stroud DA, Ryan MT. Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I. Hum Mol Genet. (2015) 24(10):2952-65 Pubmed

Lim SC, Smith KR, Stroud DA, Compton AG, Tucker EJ, Dasvarma A, Gandolfo LC, Marum JE, McKenzie M, Peters HL, Mowat D, Procopis PG, Wilcken B, Christodoulou J, Brown GK, Ryan MT, Bahlo M, Thorburn DR. A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome. Am J Hum Genet. (2014) 94(2):209-22 Pubmed

Tucker EJ, Wanschers BF, Szklarczyk R, Mountford HS, Wijeyeratne XW, van den Brand MA, Leenders AM, Rodenburg RJ, Reljić B, Compton AG, Frazier AE, Bruno DL, Christodoulou J, Endo H, Ryan MT, Nijtmans LG, Huynen MA, Thorburn DR. Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression. PLoS Genet. 2013 ;9(12):e1004034 Pubmed

Stroud DA, Formosa LE, Wijeyeratne XW, Nguyen TN, Ryan MT. Gene knockout using transcription activator-like effector nucleases (TALENs) reveals that human NDUFA9 protein is essential for stabilizing the junction between membrane and matrix arms of complex I. J Biol Chem. 2013288(3):1685-90 Pubmed

Funding:

National Health & Medical Research Council Project Grants (2014-2016; 2016-2021)

Australian Mitochondrial Disease Foundation incubator grant (2016)

Links:

Australian Mitochondrial Disease Foundation