Brain and Mitochondrial Research

Brain and Mitochondrial Research

John Christodoulou

Research Group Lead: Professor John Christodoulou | +61 3 9936 6516 | john.christodoulou@mcri.edu.au

Research Overview:

Under the campus partnership, our research is embedded in MCRI.  A full research profile may be found at https://www.mcri.edu.au/research/research-areas/genomic-medicine/brain-and-mitochondrial.

The Brain and Mitochondrial Research Group is dedicated to improving the diagnosis and outcomes for children and families affected by rare inherited diseases, particularly those affecting the normal development and function of the brain and nerves.

By studying the functions of genes, we hope to gain a better understanding of the biology of these neurodevelopmental disorders.  In collaboration with senior clinical and laboratory colleagues nationally, we have established the Australian Undiagnosed Diseases Network (UDN-Aus; https://www.udnaus.org), which is focussed on using next generation sequencing and functional analyses (including transcriptomics, proteomics, lipidomics long read sequencing and cell or animal model based functional studies),  to “solve the unsolved”, paediatric- and adult-onset complex disorders that are strongly suspected to have a monogenic basis.

We also use preclinical stem cell models to model mitochondrial diseases and other neurogenetic conditions using pluripotent stem cell technology. This allows us to reprogram patient skin cells into specific cell types. Patient-specific stem cell models enable us to study disease mechanisms and test treatment strategies.

Another major area of our research focus is the mitoHOPE Program (https://www.monash.edu/medicine/mitohope), which is a led by Professor John Carroll at Monash University, and which is piloting the introduction of mitochondrial donation into Australian clinical practice.

The program includes:

  • a clinical trial to determine the safety and efficacy of mitochondrial donation,
  • a research program to refine existing mitochondrial donation techniques, and
  • an education program to increase health practitioners' knowledge about mitochondrial disease.

The mitoHOPE Program’s clinical trial is the first of its kind in Australia, and only the second in the world. The program will build on a long-standing partnership between Monash University and Newcastle University (UK), where the world’s first mitochondrial donation clinical trial took place. The mitoHOPE Program brings together expertise and experience from both centres to provide hope to families affected by mitochondrial disease.

Finally, we also focus on developing an evidence base to translate research into clinical practice delivered within the Australian Healthcare system, where we play lead roles in local, national and international consortia.

Our work focuses on:

  • Expanding access to genomic diagnostic services
  • Supporting publicly accessible reproductive options to prevent inherited disease
  • Developing health economic evidence for new services
  • Facilitating recruitment of patients into clinical trials

Staff:

Co-Group Leaders:

  • Prof. John Christodoulou AM, Chair of Genomic Medicine
  • Prof. David Thorburn, Senior Principal Research Fellow

Team Leaders:

  • Dr Nicole van Bergen, Senior Research Fellow
  • Dr Simran Kaur, Senior Research Officer
  • Dr Alison Compton, Senior research Officer

Group Members:

  • Dr Ann Frazier, Senior Research Officer
  • Sean Massey, Research Assistant
  • Tegan Stait, Research Assistant
  • Tim Sikora, Research Assistant

Collaborators:

We partner with leading institutions worldwide, including:

  • Victorian Clinical Genetics Services (VCGS)
  • Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne
  • Monash Biomedicine Discovery Institute, Monash University, Melbourne
  • Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne
  • Molecular Neurobiology Research Laboratory, Kids Research, Children's Hospital at Westmead, Sydney
  • Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom
  • Broad Institute, Cambridge, MA, USA
  • Department of Genetics, Yale School of Medicine, New Haven, CT, USA
  • Department of Pediatrics & Clinical Genomics, Saitama Medical University, Japan
  • Department of Metabolism, Chiba Children's Hospital, Japan
  • Intractable Disease Research Center, Juntendo University, Japan
  • Center for Applied Genomics and Mitochondrial Medicine Frontier Program, Children’s Hospital of Philadelphia
  • Enzymology & Metabolism, Université du Luxembourg
  • BioFab3D, St Vincent’s Hospital
  • Great Ormond St Hospital, London
  • Boston Children’s Hospital
  • Hospital for Sick Children, Toronto
  • Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI, USA
  • Department of Translational Medicine, University of Naples "Federico II", Italy
  • Telethon Institute of Genetics and Medicine, Pozzuoli (NA), Italy
  • Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
  • New South Wales Health Pathology, Randwick, Sydney, Australia
  • Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, Australia
  • Molecular Genetics of Neurodevelopment, Department of Woman and Child Health, University of Padova, Italy
  • Queensland Children's Hospital, Brisbane, Australia
  • Genetic Services of Western Australia, Western Australia, Australia

Funding:

Thank you to our supporters.

  • National Health and Medical Research Council
  • Medical Research Futures Fund
  • US Department of Defence Congressionally Directed Medical Research Programs
  • Royal Children’s Hospital Research Foundation
  • Mito Foundation
  • Foundation for Children
  • The Orphan Disease Center (Million Dollar Bike Ride Grant Program)
  • Loulou Foundation (CDKL5 Forum Junior Fellowship)
  • RTW Charitable Foundation
  • Stafford Fox Medical Research Foundation
  • Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne

Research Publications (over the last two years):

  1. Stark, Z., Boughtwood, T., Haas, M., Braithwaite, J., Gaff, C.,  Ilias, G.I., Spurdle, A.B., Hansen, D.P., Hofmann, O., Laing, N., Metcalfe, S., Newson, A.J., Scott, H.S., Thorne,  N.,Ward, R.L., Dinger, M., Best, S., Long, J.C., Grimmond, S.M., Pearson, J., Waddell, N., Barnett, C.P., Cook, M.,  Field, M., Fielding, D., Fox, S.B., Gecz, J., Jaffe, A., Leventer, R., Lockhart, P.J., Lunke, S., Mallett, A.J., McGaughran, J., Mileshkin, L., Nones, K., Roscioli, T., Scheffer, I., Semsarian, C., Simons, C., Thomas, D.M., Thorburn, D.R., Tothill, R., White, D., Dunwoodie, S., Simpson, P.T., Phillips, P., Brion, M-J., Finlay, K., Quinn, M.C.J.,  Mattiske, T., Tudini, E., Boggs, K., Murray, S., Wells, K.,  Cannings, J., Sinclair, A.H., Christodoulou J., North, K.N. Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare. Amer J Human Genet. 2023 Mar 2;110(3):419-426, doi: 10.1016/j.ajhg.2023.01.018. PMID: 36868206.
  2. Lunke S, Bouffler SE, Patel CV, Sandaradura SA, Wilson M, Pinner J, Hunter MF, Barnett CP, Wallis M, Kamien B, Tan TY, Freckmann ML, Chong B, Phelan D, Francis D, Kassahn KS, Ha T, Gao S, Arts P, Jackson MR, Scott HS, Eggers S, Rowley S, Boggs K, Rakonjac A, Brett GR, de Silva MG, Springer A, Ward M, Stallard K, Simons C, Conway T, Halman A, Van Bergen NJ, Sikora T, Semcesen LN, Stroud DA, Compton AG, Thorburn DR, Bell KM, Sadedin S, North KN, Christodoulou J, Stark Z. Integrated multi-omics for rapid rare disease diagnosis on a national scale. Nat Med. 2023 Jul;29(7):1681-1691. doi: 10.1038/s41591-023-02401-9. Epub 2023 Jun 8. PMID: 37291213.
  3. Santos Gonzalez F, Hock DH, Thorburn DR, Mordaunt D, Williamson NA, Ang CS, Stroud DA, Christodoulou J, Goranitis I. A micro-costing study of mass-spectrometry based quantitative proteomics testing applied to the diagnostic pipeline of mitochondrial and other rare disorders. Orphanet J Rare Dis. 2024 Nov 29;19(1):443. doi: 10.1186/s13023-024-03462-w. PMID: 39609890. (JC co-last author)
  4. Hall R, Sawant V, Gu J, Sikora T, Rollo B, Velasco S, Kim J, Segev N, Christodoulou J, Van Bergen NJ. TRAPPopathies: Severe Multisystem Disorders Caused by Variants in Genes of the Transport Protein Particle (TRAPP) Complexes. Int J Mol Sci. 2024 Dec 12;25(24):13329. doi: 10.3390/ijms252413329. PMID: 39769094. (JC co-last author)
  5. Rius R, Compton AG, Baker NL, Balasubramaniam S, Best S, Bhattacharya K, Boggs K, Boughtwood T, Braithwaite J, Bratkovic D, Bray A, Brion MJ, Burke J, Casauria S, Chong B, Coman D, Cowie S, Cowley M, de Silva MG, Delatycki MB, Edwards S, Ellaway C, Fahey MC, Finlay K, Fletcher J, Frajman LE, Frazier AE, Gayevskiy V, Ghaoui R, Goel H, Goranitis I, Haas M, Hock DH, Howting D, Jackson MR, Kava MP, Kemp M, King-Smith S, Lake NJ, Lamont PJ, Lee J, Long JC, MacShane M, Madelli EO, Martin EM, Marum JE, Mattiske T, McGill J, Metke A, Murray S, Panetta J, Phillips LK, Quinn MCJ, Ryan MT, Schenscher S, Simons C, Smith N, Stroud DA, Tchan MC, Tom M, Wallis M, Ware TL, Welch AE, Wools C, Wu Y, Christodoulou J, Thorburn DR. The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses. Genet Med. 2025 Jan; 27(1):101271. doi: 10.1016/j.gim.2024.101271. Epub 2024 Sep 19. PMID: 39305161. (JC co-last author)
  6. Howell KB, White SM, McTague A, D’Gama AM, Costain G, Poduri A, Scheffer IE, Chau V, Smith LD, Stephenson SEM, Wojcik M, Davidson A, Sebire N, Sliz P, Beggs AH, Chitty LS, Cohn RD, Marshall CR, Andrews NC, North KN, Cross JH, Christodoulou J, Scherer SW (JC co-last author) International Precision Child Health Partnership (IPCHiP): an initiative to accelerate discovery and improve outcomes in rare pediatric disease. npj Genomic Medicine. NPJ Genom Med. 2025 Feb 27;10(1):13. doi: 10.1038/s41525-025-00474-8.  PMID: 40016282
  7. Hock DH, Caruana NJ, Semcesen LN, Lake NJ, Formosa LE, Amarasekera SSC, Stait T, Tregoning S, Frajman LE, Bournazos AM, Robinson DRL, Ball M, Reljic B, Ryder B, Wallis MJ, Vasudevan A, Beck C, Peters H, Lee J, Tan NB, Freckmann ML; MitoMDT Diagnostic Network for Genomics and Omics; Karlaftis V, Attard C, Monagle P, Samarasinghe A, Brown R, Bi W, Lek M, McFarland R, Taylor RW, Ryan MT, Cooper ST, Stark Z, Christodoulou J, Compton AG, Thorburn DR, Stroud DA. Untargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases. Genome Med. 2025 May 22;17(1):58. doi: 10.1186/s13073-025-01467-z. PMID: 40400026.
  8. Lunke S, Downie L, Caruana J, Kugenthiran N, De Fazio P, Hollizeck S, Bouffler SE, Amor DJ, Archibald AD, Bombard Y, Christodoulou J, Clausen M, Fagan W, Gaff C, Greaves RF, Gyngell C, Kanga-Parabia A, Lang N, Lee C, Lynch F, Marty A, Marty M, McGregor C, Riseley J, Sadedin S, Scarff K, da Cunha Torres M, Tutty E, Vang C, Wall M, Wong EM, Yeung A, Goranitis I, Best S, Vears DF, Stark Z. Feasibility, acceptability and clinical outcomes of the BabyScreen+ genomic newborn screening study. Nat Med. 2025 Oct 9. doi: 10.1038/s41591-025-03986-z. Epub ahead of print. PMID: 41068466.

Research Projects:

International Precision Child Health Partnership (IPCHiP) is the first major global collaboration, aiming to improve child health and rare disease outcomes through collaborative genomics. As an international consortium IPCHiP leverages medical and scientific expertise using genomic data to accelerate discoveries and therapeutic options.

KIF1A-Associated Neurological Disorder (KAND) research program. KAND is a rare and progressive neurodegenerative disease caused by variants in the KIF1A gene. The condition can appear in infancy or early childhood, leading to vision impairment, muscle weakness, movement difficulties, developmental delay, and seizures that may not respond to medication. The research program aims to better understand disease progression and explore potential therapeutic approaches for affected children and families.

The Leigh Syndrome Roadmap Project (LSRP) invites individuals aged 0–75 with a genetic diagnosis of Leigh Syndrome to contribute to a deeper understanding of this mitochondrial condition. The study collects both clinical and patient-reported information to build a comprehensive picture of symptom patterns and progression across the lifespan.

Precision therapies for life-threatening ultra-rare genetic diseases in children

Developing personalised medicines using genomics, stem cells and drug screening to restore brain function in children with specific ultra-rare, life-threatening genetic disorders.

Each year, around 15,000 Australian children are born with ultra-rare genetic diseases. Among these, TRAPPC4 deficiency, CDKL5 Deficiency Disorder (CDD) and NAXD deficiency are particularly devastating. Our team led the gene discovery for both NAXD and TRAPPC4 in 2019.

Multi-omic analyses of inherited metabolic disorders with ‘variants of uncertain significance’

Individual rare diseases affect fewer than 1 in 2,000 people, but collectively, more than 7,000 rare diseases impact over one million Australians. While genomic sequencing has transformed rare disease diagnosis, many cases remain unsolved, using integrated genomic and multi-omic analyses to interpret variants of uncertain significance. The goal is to provide definitive diagnoses, clarify disease mechanisms, and apply new analytical methods to unsolved cases.

Stem cell models for investigating disease mechanisms in metabolic and neurogenetic disorders

Access to affected tissues like brain and heart cells is often limited in rare disease research. To overcome this, researchers generate patient-derived pluripotent stem cells and differentiate them into neurons and cardiomyocytes (heart cells). These cell models allow investigation of disease mechanisms in the most relevant tissues, using advanced functional, transcriptomic, and proteomic analyses.

Solving the unsolved: life-changing answers for families

Rare diseases affect up to 15,000 Australian children each year. Over one-third of these families are seen at the The Royal Children’s Hospital (RCH) for diagnosis — unsurprising given that 80% of rare diseases have a genetic basis. RCH is internationally recognised for integrating genomics into clinical care.

Through projects such as the Undiagnosed Diseases Program Victoria and RDNow, we are expanding our research capacity to increase the number of families receiving a diagnosis—bringing an end to their diagnostic odyssey. We collaborate with clinicians and researchers across campus and with leading children’s hospitals worldwide to unify care pathways and accelerate the development of new therapies.

Undiagnosed Diseases Network-Australia (UDN-Aus)

Even with genomic sequencing, around half of rare disease cases remain unsolved. UDN-Aus is a national initiative that unites clinicians, researchers, and diagnostic scientists to reanalyse genomic data and apply advanced molecular techniques. The network’s mission is to raise diagnostic rates above 70% and to foster a coordinated approach to undiagnosed rare diseases across Australia.