Food is converted to energy by power plants in our cells called mitochondria. Inherited disorders of mitochondrial energy generation comprise more than 160 disorders and cause impaired physical or cognitive development, neurodegenerative disease and other disabilities, as well as death in infants or children.
This laboratory has acted as the Australasian referral centre for diagnosis of mitochondrial disease in children for more than two decades and has diagnosed more than 500 children. The lab has a high international profile for research contribution, including translating knowledge of mitochondrial DNA genetics into reproductive options for families, defining diagnostic criteria and epidemiology and improving diagnosis and discovery of new “disease” genes through Next Generation DNA sequencing. Through collaboration with the Victorian Clinical Genetics Service plus national and international colleagues, the researchers have identified mutations in more than 50 different genes, 16 of which were first identified at the Murdoch Childrens mitochondrial lab.
Researchers developed two mouse models with mitochondrial Complex I defects, which are being used to highlight pathogenic mechanisms and trial therapeutic strategies.
The group’s studies have ended the diagnostic odyssey for hundreds of families, allowed many to have healthy children, and underpinned research aiming to improve treatment for these disabling diseases.
In this fluorescent image of a cell, the mitochondrial network is labelled red and the DNA stained green. The bulk of the green staining is in the nucleus but the green spots throughout the mitochondrial network represent mitochondrial nucleoids. These contain multiple mtDNA molecules plus much of the protein machinery needed for mtDNA replication and expression. Credit: Dr Ann Frazier
Using Next Generation Sequencing to Discover Novel Genes that Cause Mitochondrial Disorders.
Mitochondria generate energy through the oxidative phosphorylation (OXPHOS) system. Mutations in over 160 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. The group’s researchers have been developing Next Generation Sequencing approaches to study more than 1000 genes known to encode mitochondrial proteins in patients with OXPHOS diseases, with recent studies identifying unique disease genes published in Nature Genetics, Cell Metabolism and Science Translational Medicine. The project will involve prioritising and following up novel sequence variants in order to discover unique disease genes and determine their normal function and disease pathogenesis using a combination of cell biology, molecular biology and biochemical approaches.
New Approaches for Prevention of Cardiac & Neurological Disease Caused by Mitochondrial Dysfunction
Severe disorders of mitochondrial energy generation cause a wide range of diseases, primarily affecting the brain and heart, which affect approximately one in 5000 individuals. Milder mitochondrial dysfunction is also implicated in the pathogenesis of common age-related neurological and cardiac diseases in the general population. Currently, no effective treatments for mitochondrial disease are available. We have characterised two unique mouse models of mitochondrial Complex I (CI) deficiency, one with primarily cardiac disease and the other with neurodegenerative disease. This project will trial treatment strategies with drugs such as rapamycin or nicotinamide riboside that target signalling pathways affected by mitochondrial dysfunction. Response to treatment will be assessed using a wide range of histological, metabolic, physiological, molecular, immunochemical, echocardiographical and neurobehavioural approaches that have been developed to assess outcome. If successful, some of these strategies could be readily translated into clinical practice to treat patients with mitochondrial disease or common conditions that involve mitochondrial dysfunction.
Pathogenic Mechanisms of Mitochondrial Dysfunction in Brain and Heart
Mitochondrial dysfunction causes a range of early-onset neurological and cardiac conditions as well as contributing to neurodegenerative conditions including Parkinson’s 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. This project will use human and mouse primary cell culture models plus induced pluripotent stem cells (stem cells generated from adults) and human embryonic stem cells that can be differentiated into cardiac or neuronal lineages. Researchers 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.
- Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I. 2015
- COA6 is a mitochondrial complex IV assembly factor critical for biogenesis of mtDNA-encoded COX2. 2015
- Delayed diagnosis of congenital myasthenia due to associated mitochondrial enzyme defect. 2015
- Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder. 2015
- IGF2BP2/IMP2-Deficient Mice Resist Obesity through Enhanced Translation of Ucp1 mRNA and Other mRNAs Encoding Mitochondrial Proteins. 2015
- Leigh Syndrome Caused by the MT-ND5 m.13513G>A Mutation: A Case Presenting with WPW-Like Conduction Defect, Cardiomyopathy, Hypertension and Hyponatraemia. 2015
- Leigh syndrome: neuropathology and pathogenesis. 2015
- Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. 2015
- N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease. 2015
- Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: A case report and literature review. 2015
- Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation. 2015
- A Founder Mutation in PET100 Causes Isolated Complex IV Deficiency in Lebanese Individuals with Leigh Syndrome. 2014
- Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. 2014
- Functional characterization of Friedreich ataxia iPS-derived neuronal progenitors and their integration in the adult brain. 2014
- Mitochondrial DNA-Associated Leigh Syndrome and NARP 2014
- Molecular diagnosis of mitochondrial respiratory chain disorders in Japan: Focusing on mitochondrial DNA depletion syndrome. 2014
- Neuronal and astrocyte dysfunction diverges from embryonic fibroblasts in the Ndufs4fky/fky mouse. 2014
- Rapid identification of a novel complex I MT-ND3 m.10134C>A mutation in a Leigh syndrome patient. 2014
- Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment. 2014
- Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models. 2014
- 189th ENMC International workshop Complex I deficiency: Diagnosis and treatment 20-22 April 2012, Naarden, The Netherlands. 2013
- 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients. 2013
- Deficiency in Mitochondrial Complex I Activity Due to Ndufs6 Gene Trap Insertion Induces Renal Disease. 2013
- Fumarase Deficiency in Dichorionic Diamniotic Twins. 2013
- Mitochondrial dysfunction in a novel form of autosomal recessive ataxia. 2013
- Modelling biochemical features of mitochondrial neuropathology. 2013
- Mutations in CYC1, Encoding Cytochrome c1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia. 2013
- Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes 2013
- Mutations in the UQCC1-Interacting Protein, UQCC2, Cause Human Complex III Deficiency Associated with Perturbed Cytochrome b Protein Expression. 2013
- SURF1 deficiency: a multi-centre natural history study. 2013
- Targeted exome sequencing of suspected mitochondrial disorders. 2013
- Variant nonketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. 2013
- A case of myelopathy, myopathy, peripheral neuropathy and subcortical grey matter degeneration associated with recessive compound heterozygous POLG1 mutations. 2012
- Biochemical analyses of the electron transport chain complexes by spectrophotometry. 2012
- Late-adult onset Leigh syndrome. 2012
- Mitochondrial respiratory chain hepatopathies: role of liver transplantation. A case series of five patients. 2012
- Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. 2012
- Next Generation Sequencing in molecular diagnosis: NUBPL mutations highlight the challenges of variant detection and interpretation. 2012
- 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. 2012
- Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy. 2012
- Toward a mtDNA locus-specific mutation database using the LOVD platform. 2012
- Treatment for mitochondrial disorders. 2012
- Understanding mitochondrial complex I assembly in health and disease. 2012
- Alpers syndrome with mutations in POLG: Clinical and investigative features 2011
- Application of oligonucleotide array CGH in the detection of a large intragenic deletion in POLG associated with Alpers Syndrome. 2011
- De novo SCN1A mutations in migrating partial seizures of infancy 2011
- 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 2011
- Mitochondrial medicine: a clinical guideline Khondrion 2011
- Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. 2011
- Mutations in the gene encoding C8orf38 block complex I assembly by inhibiting production of the mitochondria-encoded subunit ND1. 2011
- Phytanic acid metabolism in health and disease 2011
- Quality improvement of mitochondrial respiratory chain complex enzyme assays using Caenorhabditis elegans. 2011
- Respiratory chain complex I deficiency caused by mitochondrial DNA mutations 2011
- The molecular basis of human complex I deficiency. 2011