Human Stem Cell Models of Mitochondrial Disease

Research Opportunity
Royal Children’s Hospital/Murdoch Childrens Research Institute
Primary Supervisor Email Number Webpage
Professor David Thorburn +61383416235 Personal web page
Co-supervisor Email Number Webpage
Dr Ann Frazier +61399366602 Personal web page

Project Details

Mitochondria are our cellular power plants that burn sugars, fats and proteins to generate energy. Each week in Australia a child is born with a mitochondrial disorder. Many of these children die in the first years of life and most suffer from severe disease, particularly affecting their brain and/or heart. Access to these tissues from patients is limited, making it difficult to assess the impact on mitochondrial and other pathways contributing to disease pathology. This project is part of a 5-year NHMRC-funded study to develop and characterize human stem cell models for over 20 genes in which knockout-type mutations cause inherited disorders of mitochondrial energy generation.

The overall aims are:
1) Assemble a representative panel of cellular models of OXPHOS disease in human Embryonic Stem Cells (hESCs) and human Induced Pluripotent Stem Cells (iPSCs) that can be used to study phenotypic rescue of novel defects, pathogenicity and treatment approaches.
2) Characterize pathogenic pathways in the most relevant cell lineages by assessing the impact of OXPHOS defects on the mitochondrial and cellular proteome of cardiomyocytes and neural cells generated from hESCs or iPSCs, as well as the impact on mitochondrial function and cellular physiology.
3) Define the impact of targeted therapeutic strategies in these models on the cellular proteome and other markers of cellular homeostasis.

The research project will thus involve generation of hESCs with CRISPR/Cas9 mediated gene disruption, or iPCs from mitochondrial disease patient fibroblasts, followed by confirmation of the impact on the targeted gene and pathway. Selected cell lines will then be differentiated to cardiomyocyte and/or neural lineages to enable comparison (with control cells) of the impact of the gene knockout on various aspects of mitochondrial and cellular function. These may include respiration, ATP synthesis, reactive oxygen species, mitochondrial membrane potential, redox balance, cellular stress response and quantitative proteomics.

Faculty Research Themes

Child Health

School Research Themes

Child Health in Medicine

Research Opportunities

Students who are interested in joining this project will need to consider their elegibility as well as other requirements before contacting the supervisor of this research

Graduate Research application

Honours application

Key Contact

For further information about this research, please contact a supervisor.



Research Node

Royal Children’s Hospital/Murdoch Childrens Research Institute

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