Mitochondrial medicine and biology


Student project opportunities


Identifying the genetic causes of mitochondrial diseases

Research area:  genetics, cell biology and biochemistry
Chief supervisor:  Professor Aleksandra Filipovska
Other supervisors:  Dr Tara Richman and Professor Luba Kalaydjieva
Project suitable for: Honours, Masters and PhD
Essential qualifications: BSc or BSc (Hons)
Start date: anytime

Project outline  
Mitochondria are microscopic, energy producing machines that are found in all human cells. Mitochondria contain a small set of genes that must work properly to make the energy our bodies require for health. Defects in the expression of mitochondrial genes cause debilitating diseases for which there are no cures currently. We will use new genomic, molecular and cell biology technologies to identify new mutations that lead to disease and understand how the mutations cause the disease pathology at a molecular level.

Mitochondrial disease are progressive and debilitating multi-system disease that occurs as a result of mutations in nuclear or mitochondrial genes at a frequency of up to 1 in 13,000 live births with no known cure. Mutations in nuclear genes that code for mitochondrial proteins have been found to cause a range of diseases including mitochondrial diseases that have the same pathologies to those observed in patients with mutations in mtDNA. We have DNA and cells from several families that suffer from mitochondrial diseases that are not the result of mtDNA mutations but mutations in nuclear genes coding for mitochondrial proteins. This project will use patient DNA to identify mutations in nuclear genes that cause mitochondrial disease and use the patient cells to investigate how the changes at the DNA level cause mitochondrial and cellular dysfunction that leads to the disease pathology. The project will use a variety of techniques ranging from genetics, next generation technologies, molecular and cell biology. This is of great importance in understanding the mechanisms underlying mitochondrial disease and may provide new avenues for therapeutic interventions.

This project involves the use of a range of techniques in genetics, cell biology (such as cell culture, cell death assays, fluorescence microscopy, gel electrophoresis, western blotting), genomics (exome sequencing), molecular biology (cloning, quantitative PCR, RNA interference) and biochemistry (protein purification, enzyme activity measurements).

Selected publications from the lab

  1. Mercer, T.R., Neph, S., Crawford, J., Dinger, M.E., Smith, M.A., Shearwood, A.-M.J., Haugen, E., Bracken, C.P., Rackham, O., Stamatoyannopoulos, J.A., Filipovska, A. and Mattick, J.S. (2011) The human mitochondrial transcriptome. Cell 146(4): 645-658.
  2. Lopez Sanchez, M.I.G., Mercer, T.R., Davies, S.M., Shearwood, A.-M.J., Nygård, K.K.A., Richman, T.R., Mattick, J.S., Rackham, O. and Filipovska, A. (2011) RNA processing in human mitochondria. Cell Cycle 10(17): 1-13.
  3. Rackham O., Davies, S.M.K., Shearwood, A.-M.J., Hamilton, K.L., Whelan, J. and Filipovska, A. Pentatricopeptide repeat domain protein 1 lowers the levels of mitochondrial leucine tRNAs in cells (2009) Nucleic Acids Research 37(17):5859-67.
  4. Davies, S.M.K., Rackham O., Shearwood, A.-M.J., Hamilton, K.L., Narsai, R., Whelan, J. and Filipovska, A. Pentatricopeptide repeat domain protein 3 associates with the mitochondrial small ribosomal subunit and regulates translation (2009) FEBS Letters 583, 1853-8.


Contact
Professor Aleksandra Filipovska -  aleksandra.filipovska@perkins.uwa.edu.au

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Characterising the pathology of mitochondrial diseases

Research area:  metabolism, genetics, cell biology and biochemistry
Chief supervisor: Professor Aleksandra Filipovska
Other supervisors: Dr Tara Richman
Project suitable for: Honours, Masters and PhD
Essential qualifications: BSc or BSc (Hons)
Start date: anytime

Project outline
Mitochondria are microscopic, energy producing machines that are found in all human cells. Mitochondria contain a small set of genes that must work properly to make the energy our bodies require for health. Defects in the expression of mitochondrial genes cause debilitating diseases for which there are no cures currently. We have animal models of mitochondrial disease where mitochondrial gene expression is compromised and we use new genomic, molecular and cell biology technologies to identify how changes in gene expression and cause the disease pathology at a molecular level.

Mitochondrial disease are progressive and debilitating multi-system disease that occurs as a result of mutations in nuclear or mitochondrial genes at a frequency of up to 1 in 13,000 live births with no known cure. Mutations in nuclear genes that code for mitochondrial proteins have been found to cause a range of diseases including mitochondrial diseases that have the same pathologies to those observed in patients with mutations in mtDNA. We use tissues from mouse models of mitochondrial diseases to investigate how specific proteins regulate gene expression and how lack of these genes can cause lead to the disease pathology. The project will use a variety of techniques ranging from genetics, immunohistochemistry, molecular and cell biology, biochemistry and next generation sequencing. This is of great importance in understanding the mechanisms underlying mitochondrial disease and may provide new avenues for therapeutic interventions. This project involves the use of a range of techniques in genetics, cell biology (such as cell culture, cell death assays, fluorescence microscopy, gel electrophoresis, western blotting), genomics (RNA sequencing), molecular biology (cloning, quantitative PCR) and biochemistry (protein purification, enzyme activity measurements).


Selected publications from the lab

  1. Mercer, T.R., Neph, S., Crawford, J., Dinger, M.E., Smith, M.A., Shearwood, A.-M.J., Haugen, E., Bracken, C.P., Rackham, O., Stamatoyannopoulos, J.A., Filipovska, A. and Mattick, J.S. (2011) The human mitochondrial transcriptome. Cell 146(4): 645-658.
  2. Lopez Sanchez, M.I.G., Mercer, T.R., Davies, S.M., Shearwood, A.-M.J., Nygård, K.K.A., Richman, T.R., Mattick, J.S., Rackham, O. and Filipovska, A. (2011) RNA processing in human mitochondria. Cell Cycle 10(17): 1-13.
  3. Richman, T.R., Davies, S.M.K., Shearwood, A-M.J., Ermer, J.A., Scott, L.H., Hibbs, M.E., Rackham, O. and Filipovska, A. (2014) A bifunctional protein regulates mitochondrial protein synthesis. Nucleic Acids Research doi: 10.1093/nar/gku179
  4. Liu, G., Mercer, T.R., Shearwood, A.-M.J., Siira, S.J., Hibbs, M.E., Mattick, J.S., Rackham, O. and Filipovska, A. (2013) Mapping of mitochondrial RNA-protein interactions by digital RNase footprinting. Cell Reports 5(3):839-48.


Contact
Professor Aleksandra Filipovska  - aleksandra.filipovska@perkins.uwa.edu.au

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The role of mitochondrial function in diabetes and obesity

Research area: Genetics, cell biology and biochemistry
Chief supervisor: Professor Aleksandra Filipovska
Other supervisors: Dr Tara Richman
Project suitable for: Honours, Masters and PhD
Essential qualifications: BSc or BSc (Hons)
Start date: anytime

Project outline
Excess weight and obesity are major risk factors for insulin resistance and type 2 diabetes. The prevalence of glucose intolerance in response to excess weight among Australians has been increasing for the past 30 years. Fat consumed in our diet is broken down to produce energy that our bodies require by the cellular energy plants know as mitochondria. In addition to fat, mitochondria degrade carbohydrates and regulate the overall energy production in our bodies’ cells. If the function of mitochondria is compromised or damaged the degradation of fat and carbohydrates is misregulated.

This project will investigate a mutation in a mitochondrial gene that is required for energy production and breakdown of fats and carbohydrates. Recently we have found that this mutation slows down the breakdown of fats and as a result leads to insulin resistance, fatty liver and obesity. We are interested to understand how a single mutation can impair energy metabolism and lead to insulin resistance. Insight into this process would enable us to develop specific drugs and treatments that can overcome the impact of insulin resistance on normal body function.

This project involves the use of a range of techniques in genetics, mouse pathology and physiology, cell biology (such as cell culture, cell death assays, fluorescence microscopy, gel electrophoresis, western blotting), molecular biology (cloning, quantitative PCR, RNA interference) and biochemistry (protein purification, enzyme activity measurements).

Contact
Professor Aleksandra Filipovska  - aleksandra.filipovska@uwa.edu.au

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