Mitochondrial Research

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
Group Members: 

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.

  • Professor Michael Ryan, La Trobe University 
  • Professor John Christodoulou, Children’s Hospital, Westmead, Sydney 
  • Professor Vamsi Mootha, Massachusetts General Hospital