Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$285,990.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin i ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin is down-regulated by either erythroid differentiation or the haem precursor protoporphyrin IX (Becker and Richardson, submitted). These data strongly suggest a role for frataxin in iron metabolism. In the present study we will continue to assess if frataxin plays a role in the way cells handle iron. Using a unique model of mitochondrial iron overload developed in my lab (Richardson et al. (1996) BLOOD 87:3477), we will extensively investigate the iron metabolism of the mitochondrion in order to determine the function of frataxin and its role in Friedreich's ataxia. In addition, we have developed a series of new drugs known as iron chelators that can enter the mitochondrion due to their high lipid solubility (Becker and Richardson 1999 J. Lab. Clin. Med. 134:510). These latter drugs are far more effective than the chelator currently used to treat iron overload, desferrioxamine (DFO). Indeed, our chelators have been designed to result in high iron chelation efficacy but low toxicity (see Becker and Richardson, 1999). This exciting research may be crucial in understanding the development of FA and in creating new therapies such as the use of iron chelators.Read moreRead less
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$606,000.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that c ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that cause severe damage. Further, cells deficient in frataxin are sensitive to oxidant stress and Fe chelators rescue oxidant-mediated death of cells from FA patients. Indeed, free radical scavengers have shown to be of use in the treatment of this disease. Studies in DR's lab during this NHMRC grant have shown that frataxin is down-regulated by erythroid differentiation or the haem precursor, protoporphyrin IX (BLOOD 2002;99:3813-22). These data indicate a role for frataxin in Fe metabolism and the pathogenesis of FA. In this study we will continue to examine the role of frataxin in the way cells handle Fe using experimental models developed under the current NHMRC grant. These include transfected cell lines with low frataxin expression generated using an expression vector containing anti-sense frataxin cDNA. Further we obtained the frataxin conditional KO mouse and generated a breeding colony. These animals display many of the pathological features of FA and are the best current model of the disease. Indeed, they will be critical for assessing the role of frataxin in Fe metabolism and as a model to test the ability of Fe-binding drugs to prevent the pathology observed. We designed lipid-soluble chelators that can enter the mitochondrion to bind Fe (Biochim Biophys Acta 2001;1536:133-140) and these ligands will be tested to prevent disease progression in the KO mice. This exciting research is crucial for understanding the pathogenesis of FA and in creating new therapies.Read moreRead less
Ecosystem resilience of Shark Bay under changing ocean climate. This project aims to investigate the resilience of the Shark Bay World Heritage Site to projected climate change. This project will generate new knowledge for marine conservation through analyses of habitat loss on nutrient budgets and productivity in seagrass and microbialite ecosystems. Expected outcomes are an improved understanding of climate-driven shifts on ecosystem processes in Shark Bay, incorporating science-based evidence ....Ecosystem resilience of Shark Bay under changing ocean climate. This project aims to investigate the resilience of the Shark Bay World Heritage Site to projected climate change. This project will generate new knowledge for marine conservation through analyses of habitat loss on nutrient budgets and productivity in seagrass and microbialite ecosystems. Expected outcomes are an improved understanding of climate-driven shifts on ecosystem processes in Shark Bay, incorporating science-based evidence for better conservation and management. This will provide significant benefits by contributing to the future-proofing of Shark Bay’s World Heritage values to climate change, and more broadly by demonstrating the consequences of the continued tropicalisation of Australia’s coastline.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE130100203
Funder
Australian Research Council
Funding Amount
$385,000.00
Summary
Autonomous benthic observing system. This project seeks to improve our ability to monitor marine habitats and characterise their variability by enhancing the Integrated Marine Observing system (IMOS) Autonomous Underwater Vehicle (AUV) Facility. The new AUV infrastructure will reduce operating costs, increase robustness of the sampling effort and insure continued operation for the next decade.
ARC Centre of Excellence for Children and Families over the Life Course. New solutions are needed to underpin the Australian social ideal of a fair go, and to drive future global economic productivity. The Australian Productivity Commission identifies deep and persistent disadvantage as a significant problem in Australia given the failure of growing national prosperity over the past two decades to benefit underprivileged Australians. Social disadvantage is a global challenge. This Centre will ad ....ARC Centre of Excellence for Children and Families over the Life Course. New solutions are needed to underpin the Australian social ideal of a fair go, and to drive future global economic productivity. The Australian Productivity Commission identifies deep and persistent disadvantage as a significant problem in Australia given the failure of growing national prosperity over the past two decades to benefit underprivileged Australians. Social disadvantage is a global challenge. This Centre will advance basic, applied and translational research to reduce intergenerational and long-term disadvantage. Through the maturation of longitudinal datasets and advanced data integration we can follow the journeys of Australian families over generations and across the life course. This data will provide evidence for new policies and make a real difference to the lives of children and families.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE170100219
Funder
Australian Research Council
Funding Amount
$170,000.00
Summary
A multi-institutional environmental radioactivity research centre. This project aims to establish an environmental radioactivity research centre, equipped with ultra-low background and high-resolution alpha and gamma spectrometry systems, radon detectors and radium delayed coincidence counters. The centre will address a critical demand in Australia for precise analysis of a large suite of natural and artificial radionuclides, which will be used as tracers and chronological tools to investigate k ....A multi-institutional environmental radioactivity research centre. This project aims to establish an environmental radioactivity research centre, equipped with ultra-low background and high-resolution alpha and gamma spectrometry systems, radon detectors and radium delayed coincidence counters. The centre will address a critical demand in Australia for precise analysis of a large suite of natural and artificial radionuclides, which will be used as tracers and chronological tools to investigate key questions in oceanography and the mining and energy, archaeological, agricultural, and forestry sectors. The facility is expected to substantially increase expertise and training in radionuclides in Australia, and promote high-level research collaborations and outputs of both national and international significance. Major outcomes of the proposed facility include better understanding of how oceans regulate climate and improved capacity to assess effects of radiation on natural ecosystems.Read moreRead less
Modern human origins and early behavioural complexity in Australia and Southeast Asia. This project tackles a fundamental issue in world prehistory: how and when did humans first cross from Southeast Asia into Australia. Three new archaeological excavations using novel methods of analysis will assess the nature of behavioural complexity and human evolution at the time when Australia was first colonised over 45,000 years ago.
ARC Centre of Excellence for Green Electrochemical Transformation of Carbon Dioxide. ARC Centre of Excellence for Green Electrochemical Transformation of Carbon Dioxide. This Centre aims to advance carbon dioxide electrochemistry innovations to enable the conversion of carbon dioxide into valuable products and transition Australia to a carbon-neutral economy. This Centre expects to generate new knowledge using experimental and computational approaches to develop systems-level understanding to fu ....ARC Centre of Excellence for Green Electrochemical Transformation of Carbon Dioxide. ARC Centre of Excellence for Green Electrochemical Transformation of Carbon Dioxide. This Centre aims to advance carbon dioxide electrochemistry innovations to enable the conversion of carbon dioxide into valuable products and transition Australia to a carbon-neutral economy. This Centre expects to generate new knowledge using experimental and computational approaches to develop systems-level understanding to furnish industry-ready carbon dioxide utilisation technologies. Expected outcomes include enhanced capacity through collaborations establishing the Centre as an international hub for research, training, technology translation and strategic advice for stakeholders and policymakers. This should accelerate Australia’s progress towards net zero emissions targets and grow a sustainable economy and create future jobs.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100112
Funder
Australian Research Council
Funding Amount
$275,000.00
Summary
A Raman facility for advanced research supporting Australia’s natural gas, oil, coal and minerals industries. This modern Raman Spectroscopy facility will support the science and engineering that underpins the production and processing of Australia’s natural resources. Using high-pressure fibre optics, novel lasers and advanced imaging, the facility will enable the monitoring and improvement of processes and materials under extreme conditions.