research

mitochondrial research

summary

Food is converted to energy by power plants in our cells called mitochondria. Hundreds of genes are needed for the energy generating pathways to work properly, and severe mitochondrial problems cause impaired physical or cognitive development, neurodegenerative disease and other disabilities, as well as death in infants or children. Milder disorders can cause symptoms in adults such as diabetes, deafness, strokes, heart disease and dementia.

Our research extends from being the Australasian referral centre for diagnosis of these disorders in children through to identifying the genetic basis and the specific mechanisms causing disease. We aim to improve reproductive options for families and to develop new approaches for effective therapy.

group leader(s)

Thorburn 4

  Professor David Thorburn
  Murdoch Childrens Research Institute
  Royal Children's Hospital
  Flemington Road
  Parkville
  Victoria, 3052
  Australia

  T +61 3 8341 6235
  F +61 3 8341 6212
  E david.thorburn@mcri.edu.au

group leader biography

current research projects

Project 1: Using Next Generation Sequencing to Discover Novel Genes that Cause Mitochondrial Disorders

Mitochondria generate energy through the oxidative phosphorylation (OXPHOS) system. Mutations in over 100 genes required for correct assembly and function of the five OXPHOS protein complexes result in a variety of neurodegenerative disorders collectively known as mitochondrial disorders. We have been developing Next Generation Sequencing approaches to study the more than 1000 genes known to encode mitochondrial proteins in patients with OXPHOS diseases, with our most recent studies identifying novel disease genes published in Nature Genetics and Cell Metabolism. These studies also involve extensive experimental work using a combination of cell biology, molecular biology and biochemical approaches to investigate function and pathogenesis of novel disease genes.

Project 2: Mouse models for mitochondrial disease: Mendelian genetics and synergistic heterozygosity

Increasing evidence suggests that some patients with mitochondrial disease have digenic or multigenic disorders rather than simple single gene defects of one mtDNA or nuclear gene. We have generated two mouse models of Complex I deficiency, the most common type of mitochondrial disease, one with a systemic Complex I defect and neurodegenerative disease and another with primarily cardiomyopathy. This project will complete characterisation of the phenotype of heterozygous and homozygous mice using a range of physiological, molecular, immunochemical and neuropathological approaches. Homozygous mice will be used in studies of therapeutic approaches such as high fat diet or upregulation of mitochondrial biogenesis. Heterozygous mice and mice heterozygous for both genes will be used to investigate synergistic heterozygosity and the role of mild mitochondrial dysfunction as a risk factor for common diseases.

Project 3: Neuropathogenic mechanisms of mitochondrial dysfunction

Mitochondrial dysfunction causes a range of early-onset neurological conditions and contributes to neurodegenerative conditions such as Parkinson Disease. The mechanisms of neuronal damage are unknown, and the study of these at a cellular level may lead to improved treatment and greater understanding of the role of both nuclear- and mitochondrial-DNA mutations in both rare and common conditions. Using human and mouse primary cell culture models plus iPS cells, this project will study the effects of mutations on mitochondrial membrane potential, reactive oxygen species, ATP production, apoptosis and cellular calcium dynamics, primarily using techniques in fluorescent microscopy and cell biology, as well as biochemistry and molecular biology. In particular, it will focus on primary neural cell cultures established from two mouse models with complex I deficiency.

team members

  • Matt Bird - PhD Student (UoM Paeds)
  • Karen Canavan - Technical Assistant
  • Alison Compton - Postdoctoral Fellow
  • Alysha Eibl-Geldart - Honours Student (UoM Paeds)
  • Ann Frazier - Postdoctoral Fellow
  • Bi-xia Ke - Postdoctoral Fellow
  • Jasper Komen - Postdoctoral Fellow
  • Adrienne Laskowski - Research Assistant
  • Sze Chern Lim - RESEARCH ASSISTANT
  • Justine Marum - Research Assistant
  • Hayley Mountford - PhD Student (UoM Paeds)
  • Erin Oldaker - Research Assistant
  • Wendy Salter - Research Assistant
  • Simone Tregoning - Research Assistant
  • Elena Tucker - Research Officer

publications

  • Carranza Rojo DC., Hamiwka L., McMahon JM., Dibbens LM., Arsov T., Suls A., Stodberg T., Kelley K., Wirrell E., Appleton B., Mackay M., Freeman JL., Yendle SC., Berkovic SF., Bienvenu T., De Jonghe P., Thorburn DR., Mulley JC., Mefford HC., Scheffer IE. De novo SCN1A mutations in migrating partial seizures of infancy. NEUROLOGY 77 (4) : 380 - 383(2011) PubMed
  • Chen X., Thorburn DR., Wong LJ., Vladutiu GD., Haas RH., Le T., Hoppel C., Sedensky M., Morgan P., Hahn SH. Quality improvement of mitochondrial respiratory chain complex enzyme assays using Caenorhabditis elegans. GENETICS IN MEDICINE 13 (9) : 794 - 799(2011) PubMed
  • De Greef E., Christodoulou J., Alexander IE., Shun A., O’Loughlin EV., Thorburn DR., Jermyn V., Stormon MO. Mitochondrial respiratory chain hepatopathies: role of liver transplantation. A case series of five patients. JMID Reports (2011)
  • Hunter MF., Peters H., Salemi R., Thorburn D., MacKay MT. Alpers syndrome with mutations in POLG: Clinical and investigative features. Pediatric Neurology 45 (5) : 311 - 318(2011)
  • McKenzie M., Tucker EJ., Compton AG., Lazarou M., George C., Thorburn DR., Ryan MT. Mutations in the gene encoding C8orf38 block complex I assembly by inhibiting production of the mitochondria-encoded subunit ND1. Journal of molecular biology 414 (3) : 413 - 426(2011) PubMed
  • Mill P., Lockhart PJ., Fitzpatrick E., Mountford HS., Hall EA., Reijns MAM., Keighren M., Bahlo M., Bromhead CJ., Budd P., Aftimos S., Delatycki MB., Savarirayan R., Jackson IJ., Amor DJ. Human and Mouse Mutations in WDR35 Cause Short-Rib Polydactyly Syndromes Due to Abnormal Ciliogenesis. American Journal of Human Genetics 88 (4) : 508 - 515(2011) PubMed
  • Mimaki M., Wang X., McKenzie M., Thorburn DR., Ryan MT. Understanding mitochondrial complex I assembly in health and disease. BIOCHIMICA ET BIOPHYSICA ACTA (2011) PubMed
  • Swalwell H., Kirby DM., Blakely EL., Mitchell A., Salemi R., Sugiana C., Compton AG., Tucker EJ., Ke X., Lamont PJ., Turnbull DM., McFarland R., Taylor RW., Thorburn DR. Respiratory chain complex I deficiency caused by mitochondrial DNA mutations. EUROPEAN JOURNAL OF HUMAN GENETICS 19 (7) : 769 - 775(2011) PubMed
  • Tucker EJ., Compton AG., Calvo SE., Thorburn DR. The molecular basis of human complex I deficiency. IUBMB Life 63 (9) : 669 - 677(2011) PubMed
  • Tucker EJ., Hershman SG., Köhrer C., Belcher-Timme CA., Patel J., Goldberger OA., Christodoulou J., Silberstein JM., McKenzie M., Ryan MT., Compton AG., Jaffe JD., Carr SA., Calvo SE., RajBhandary UL., Thorburn DR., Mootha VK. Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Cell Metabolism 14 (3) : 428 - 434(2011) PubMed
  • Tucker EJ., Mimaki M., Compton AG., McKenzie M., Ryan MT., Thorburn DR. Next Generation Sequencing in molecular diagnosis: NUBPL mutations highlight the challenges of variant detection and interpretation. HUMAN MUTATION (2011) PubMed
  • Wanders RJA., Komen J., Ferdinandusse S. Phytanic acid metabolism in health and disease. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS 1811 (9) : 498 - 507(2011) PubMed

competitive funding

National Health & Medical Research Council
Financial Markets Foundation for Children
Australian Mitochondrial Disease Foundation
Muscular Dystrophy Association (USA)
Juvenile Diabetes Research Foundation (USA)

collaborations & affiliations

Prof. Mike Ryan, Biochemistry Department, La Trobe University
Prof. Vamsi Mootha, Broad Institute of MIT and Harvard, Department of Systems Biology, Harvard University and Massachusetts General Hospital
Prof. John Christodoulou, Western Sydney Genetics Program, the Childrens Hospital at Westmead and University of Sydney
Prof. Justin St.John, Monash Institute of Medical Research
Drs Joe Smolich and Sal Pepe, Murdoch Childrens Research Institute Heart Research Group
A/Prof. Avihu Boneh, Genetic Health Services Victoria and Murdoch Childrens Research Institute Metabolic Research Group