mitochondrial research


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
  Theme Director - Genetic Disorders
  Murdoch Childrens Research Institute
  Department of Paediatrics, University of Melbourne
  Royal Children's Hospital
  Flemington Road
  Victoria, 3052
  T +61 3 8341 6235

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

  • Karen Canavan - Technical Assistant
  • Cw Chow - HONORARY FELLOW (on-campus)
  • Alison Compton - Senior Research Officer
  • Ann Frazier - Postdoctoral Fellow
  • Sophia Frentz - PhD Student
  • Helen Godsall - Personal Assistant
  • Bi-xia Ke - Postdoctoral Fellow
  • Khodadad Khodadadi - PhD
  • Nicole Lake - PhD Student
  • Adrienne Laskowski - Research Assistant
  • Hayley Mountford - PhD Student (UoM Paeds)
  • Erin Oldaker - Research Assistant
  • Pieter Spincemaille - Visiting Academic
  • Tegan Stait - Research Assistant
  • Simone Tregoning - Research Assistant


Journal Article

  • Lopes Costa A., Le Bachelier C., Mathieu L., Rotig A., Boneh A., De Lonlay P., Tarnopolsky MA., Thorburn DR., Bastin J., Djouadi F. Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. HUMAN MOLECULAR GENETICS 23 : 2106 - 2119(2014) PubMed
  • Yamazaki T., Murayama K., Compton AG., Sugiana C., Harashima H., Amemiya S., Ajima M., Tsuruoka T., Fujinami A., Kawachi E., Kurashige Y., Matsushita K., Wakiguchi H., Mori M., Iwasa H., Okazaki Y., Thorburn DR., Ohtake A. Molecular diagnosis of mitochondrial respiratory chain disorders in Japan: focusing on mitochondrial DNA depletion syndrome. Pediatrics international : official journal of the Japan Pediatric Society 56 (2) : 180 - 7(2014) PubMed
  • Bird MJ., Needham K., Frazier AE., van Rooijen J., Leung J., Hough S., Denham M., Thornton ME., Parish CL., Nayagam BA., Pera M., Thorburn DR., Thompson LH., Dottori M. Functional characterization of Friedreich ataxia iPS-derived neuronal progenitors and their integration in the adult brain. PLOS ONE 9 (7) : e101718 (2014) PubMed
  • Thorburn, DR., Rahman, S. Mitochondrial DNA-Associated Leigh Syndrome and NARP. GENEREVIEWS (2014)
  • Komen JC., Thorburn DR. Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models. British Journal of Pharmacology 171 (8) : 1818 - 36(2014) PubMed
  • Miller DK., Menezes MJ., Simons C., Riley LG., Cooper ST., Grimmond SM., Thorburn DR., Christodoulou J., Taft RJ. Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. PLOS ONE 9 (8) : e104879 (2014) 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. American Journal of Human Genetics 94 : 209 - 222(2014) PubMed
  • van Dongen S., Brown RM., Brown GK., Thorburn DR., Boneh A. Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment. JIMD reports (2014) PubMed
  • Lim SC., Friemel M., Marum JE., Tucker EJ., Bruno DL., Riley LG., Christodoulou J., Kirk EP., Boneh A., Degennaro C., Springer M., Mootha VK., Rouault TA., Leimkuhler S., Thorburn DR., Compton AG. Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. HUMAN MOLECULAR GENETICS 22 (22) : 4460 - 4473(2013)
  • Baker PR., Friederich MW., Swanson MA., Shaikh T., Bhattacharya K., Scharer GH., Aicher J., Creadon-Swindell G., Geiger E., Maclean KN., Lee WT., Deshpande C., Freckmann ML., Shih LY., Wasserstein M., Rasmussen MB., Lund AM., Procopis P., Cameron JM., Robinson BH., Brown GK., Brown RM., Compton AG., Dieckmann CL., Collard R., Coughlin CR., Spector E., Wempe MF., Van Hove JL. Variant nonketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain : a journal of neurology 137 : 366 - 379(2013) PubMed
  • Tucker EJ., Wanschers BF., Szklarczyk R., Mountford HS., Wijeyeratne XW., van den Brand MA., Leenders AM., Rodenburg RJ., Reljic 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 GENETICS 9 (12) : e1004034 (2013) PubMed
  • Forbes JM., Ke BX., Nguyen TV., Henstridge DC., Penfold SA., Laskowski A., Sourris KC., Groschner LN., Cooper ME., Thorburn DR., Coughlan MT. Deficiency in Mitochondrial Complex I Activity Due to Ndufs6 Gene Trap Insertion Induces Renal Disease. Antioxidants & redox signaling 19 : 331 - 343(2013) PubMed
  • Rahman S., Thorburn DR. 189th ENMC International workshop Complex I deficiency: Diagnosis and treatment 20-22 April 2012, Naarden, The Netherlands. Neuromuscular disorders : NMD 23 : 506 - 515(2013) PubMed
  • Lieber DS., Calvo SE., Shanahan K., Slate NG., Liu S., Hershman SG., Gold NB., Chapman BA., Thorburn DR., Berry GT., Schmahmann JD., Borowsky ML., Mueller DM., Sims KB., Mootha VK. Targeted exome sequencing of suspected mitochondrial disorders. NEUROLOGY 80 (19) : 1762 - 1770(2013) PubMed
  • Murad NA., Cullen JK., McKenzie M., Ryan MT., Thorburn D., Gueven N., Kobayashi J., Birrell G., Yang J., Dörk T., Becherel O., Grattan-Smith P., Lavin MF. Mitochondrial dysfunction in a novel form of autosomal recessive ataxia. Mitochondrion 13 (3) : 235 - 45(2013) PubMed
  • Wortmann SB., Kluijtmans LA., Rodenburg RJ., Sass JO., Nouws J., van Kaauwen EP., Kleefstra T., Tranebjaerg L., de Vries MC., Isohanni P., Walter K., Alkuraya FS., Smuts I., Reinecke CJ., van der Westhuizen FH., Thorburn D., Smeitink JA., Morava E., Wevers RA. 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients. JOURNAL OF INHERITED METABOLIC DISEASE 36 : 913 - 921(2013) PubMed
  • Wedatilake Y., Brown R., McFarland R., Yaplito-Lee J., Morris AA., Champion M., Jardine PE., Clarke A., Thorburn DR., Taylor RW., Land JM., Forrest K., Dobbie A., Simmons L., Aasheim ET., Ketteridge D., Hanrahan D., Chakrapani A., Brown GK., Rahman S. SURF1 deficiency: a multi-centre natural history study. ORPHANET JOURNAL OF RARE DISEASES 8 (1) : 96 (2013) PubMed
  • Gaignard P., Menezes M., Schiff M., Bayot A., Rak M., Ogier de Baulny H., Su CH., Gilleron M., Lombes A., Abida H., Tzagoloff A., Riley L., Cooper ST., Mina K., Sivadorai P., Davis MR., Allcock RJ., Kresoje N., Laing NG., Thorburn DR., Slama A., Christodoulou J., Rustin P. Mutations in CYC1, Encoding Cytochrome c1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia. American Journal of Human Genetics 93 (2) : 384 - 389(2013) PubMed
  • Bird MJ., Thorburn DR., Frazier AE. Modelling biochemical features of mitochondrial neuropathology. BIOCHIMICA ET BIOPHYSICA ACTA 1840 : 1380 - 1392(2013) PubMed
  • Tregoning S., Salter W., Thorburn DR., Durkie M., Panayi M., Wu JY., Easterbrook A., Coman DJ. Fumarase Deficiency in Dichorionic Diamniotic Twins. Twin research and human genetics : the official journal of the International Society for Twin Studies : 1 - 4(2013) PubMed
  • Yamazaki T., Murayama K., Compton AG., Sugiana C., Harashima H., Amemiya S., Ajima M., Tsuruoka T., Fujinami A., Kawachi E., Kurashige Y., Matsushita K., Wakiguchi H., Mori M., Iwasa H., Okazaki Y., Thorburn DR., Ohtake A. Molecular diagnosis of mitochondrial respiratory chain disorders in Japan: Focusing on mitochondrial DNA depletion syndrome. Pediatrics international : official journal of the Japan Pediatric Society (2013) PubMed
  • McKelvie P., Infeld B., Marotta R., Chin J., Thorburn D., Collins S. Late-adult onset Leigh syndrome. JOURNAL OF CLINICAL NEUROSCIENCE 19 (2) : 195 - 202(2012) PubMed
  • Pfeffer G., Majamaa K., Turnbull DM., Thorburn D., Chinnery PF. Treatment for mitochondrial disorders. Cochrane database of systematic reviews (Online) 4 : CD004426 (2012) 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. JIMD reports 4 : 5 - 11(2012) 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 33 : 411 - 418(2012) PubMed
  • Elson JL., Sweeney MG., Procaccio V., Yarham JW., Salas A., Kong QP., van der Westhuizen FH., Pitceathly RD., Thorburn DR., Lott MT., Wallace DC., Taylor RW., McFarland R. Toward a mtDNA locus-specific mutation database using the LOVD platform. HUMAN MUTATION (2012) PubMed
  • Ke BX., Pepe S., Grubb DR., Komen JC., Laskowski A., Rodda FA., Hardman BM., Pitt JJ., Ryan MT., Lazarou M., Koleff J., Cheung MM., Smolich JJ., Thorburn DR. Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America 109 (16) : 6165 - 70(2012) PubMed
  • Leong DW., Komen JC., Hewitt CA., Arnaud E., McKenzie M., Phipson B., Bahlo M., Laskowski A., Kinkel SA., Davey GM., Heath WR., Voss AK., Zahedi RP., Pitt JJ., Chrast R., Sickmann A., Ryan MT., Smyth GK., Thorburn DR., Scott HS. Proteomic and metabolomic analyses of mitochondrial complex I-deficient mouse model generated by spontaneous B2 short interspersed nuclear element (SINE) insertion into NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene. The Journal of biological chemistry 287 (24) : 20652 - 63(2012) PubMed
  • Calvo SE., Compton AG., Hershman SG., Lim SC., Lieber DS., Tucker EJ., Laskowski A., Garone C., Liu S., Jaffe DB., Christodoulou J., Fletcher JM., Bruno DL., Goldblatt J., DiMauro S., Thorburn DR., Mootha VK. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Science translational medicine 4 (118) : 118ra10 (2012) PubMed
  • Mimaki M., Wang X., McKenzie M., Thorburn DR., Ryan MT. Understanding mitochondrial complex I assembly in health and disease. BIOCHIMICA ET BIOPHYSICA ACTA 1817 : 851 - 62(2012) PubMed
  • Frazier AE., Thorburn DR. Biochemical analyses of the electron transport chain complexes by spectrophotometry. Methods in molecular biology (Clifton, N.J.) 837 : 49 - 62(2012) PubMed
  • McKelvie P., Marotta R., Thorburn DR., Chin J., Punchihewa S., Collins S. A case of myelopathy, myopathy, peripheral neuropathy and subcortical grey matter degeneration associated with recessive compound heterozygous POLG1 mutations. Neuromuscular disorders : NMD 22 (5) : 401 - 5(2012) PubMed
  • 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
  • Compton AG., Troedson C., Wilson M., Procopis PG., Li FY., Brundage EK., Yamazaki T., Thorburn DR., Wong LJ. Application of oligonucleotide array CGH in the detection of a large intragenic deletion in POLG associated with Alpers Syndrome. Mitochondrion 11 (1) : 104 - 7(2011) PubMed
  • 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)
  • Loesch DZ., Godler DE., Evans A., Bui QM., Gehling F., Kotschet KE., Trost N., Storey E., Stimpson P., Kinsella G., Francis D., Thorburn DR., Venn A., Slater HR., Horne M. Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism. GENETICS IN MEDICINE 13 (5) : 392 - 399(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
  • 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
  • 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
  • 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
  • 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

Technical Paper

  • Hirano M., Lombes A., Rahman S., Shoubridge E., Smuts I., Thorburn D., Turnbull D., Wartiovaara-Suomalainen A., Zeman J., Zeviani M. Mitochondrial medicine: a clinical guideline. In: Koene S., Smeitink J.. Mitochondrial Medicine: A Clinical Guideline 1 Khondrion, Nijmegen, the Netherlands (2011)

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