Home  >  Research  >  Labs  >  Molecular Medicine Division  >  MITOCHONDRIAL MEDICINE AND BIOLOGY

CURRENT RESEARCH PROJECTS

Project

Mitochondrial RNA-binding proteins and their role in mitochondrial gene expression.

Project

Mitochondrial RNA-binding proteins and their role in mitochondrial gene expression.

Project Outline

Mitochondria play a fundamental role in cell and energy metabolism and consequently mitochondrial dysfunction can lead to severe multi-system disorders with wide range of clinical presentations that commonly include neurodegeneration, muscle defects and exercise intolerance. To understand these conditions better and identify therapeutic targets it is necessary to understand how gene expression is regulated within mitochondria, as some of the most significant gaps in our knowledge of mitochondrial function and disease are in the regulation of mitochondrial gene expression. Links between transcription and translation in mammalian mitochondria are not well understood.

Fig 1. Mitochondrial mRNAs are transcribed as part of long primary transcripts that generally encompass the entire mtDNA, therefore the ratios of the 11 mammalian mitochondrial mRNAs and their proteins are controlled post-transcriptionally. Little is known about how these 11 mRNAs are regulated in mammalian mitochondria. This is particularly important since tissue-, cell- and disease-specific variations in expression of mitochondrial RNAs has been observed, but cannot be explained at present. The basic components and mechanisms of transcription have recently been discovered, however the control of mRNA processing, translation and stability remains unclear.

We are interested in identifying mammalian mitochondrial RNA-binding proteins and investigating their role in RNA metabolism in cells. Discovery of proteins and the RNAs they bind may shed light on the regulation of gene expression in mammalian mitochondria. In addition, we are developing new methods for the identification of mitochondrial RNAs bound by the mitochondrial RNA-binding proteins that may regulate their expression in health and in disease.

Identification of mutations that cause mitochondrial disease

Mitochondrial diseases are progressive and debilitating multi-system disorders that occur as a result of mutations in nuclear or mitochondrial genes with no known cures to date. The clinical heterogeneity in mitochondrial disorders is complemented by genetic heterogeneity, where mutations in mitochondrial or nuclear genes cause similar phenotypes thus complicating mutation identification. We use next generation technologies to identify mutations in DNA from patients that suffer from mitochondrial diseases to identify the mutations that cause these diseases. We use patient cells to investigate how mutations in mitochondrial genes cause the molecular changes that cause mitochondrial and cellular dysfunction that leads to the disease pathology.

CURRENT STUDENT PROJECTS

Student Project

Identifying the genetic causes of mitochondrial diseases

Student Project

Identifying the genetic causes of mitochondrial diseases

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).

Contact
Professor Aleksandra Filipovska – [email protected]

Chief supervisor
Professor Aleksandra Filipovska

Other supervisor
Dr Tara Richman and Professor Luba Kalaydjieva

Project suitable for
Honours, Masters and PhD

Essential qualifications
BSc or BSc (Hons)

Student Project

Characterising the pathology of mitochondrial diseases

Student Project

Characterising the pathology of mitochondrial diseases

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).

Contact
Professor Aleksandra Filipovska – [email protected]

Chief supervisor
Professor Aleksandra Filipovska

Other supervisor
Dr Tara Richman

Project suitable for
Honours, Masters and PhD

Essential qualifications
BSc or BSc (Hons)

Start date
anytime

Student Project

Characterising the pathology of mitochondrial diseases

Student Project

Characterising the pathology of mitochondrial diseases

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 – [email protected]

Chief supervisor
Professor Aleksandra Filipovska

Other supervisor
Dr Tara Richman

Project suitable for
Honours, Masters and PhD

Essential qualifications
BSc or BSc (Hons)

Start date
anytime