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
Understanding multi-scale dynamics of eddies in the East Australian Current. This project aims to provide the first rigorous quantification of the complex dynamics of rotating eddies (the weather systems of the ocean) and fronts on scales ranging from metres to 100s of kilometres and hours to weeks in the East Australian Current System. This project is at the frontier of oceanographic research and will provide significant new understanding of the physical and biogeochemical dynamics of eddies an ....Understanding multi-scale dynamics of eddies in the East Australian Current. This project aims to provide the first rigorous quantification of the complex dynamics of rotating eddies (the weather systems of the ocean) and fronts on scales ranging from metres to 100s of kilometres and hours to weeks in the East Australian Current System. This project is at the frontier of oceanographic research and will provide significant new understanding of the physical and biogeochemical dynamics of eddies and their interactions across multiple spatio-temporal scales, revealing their impacts on productivity along Australia’s most populous coastline. This will provide significant benefits such as improved ocean forecasting and sustainable management of Australian marine industries and seafood sector, supporting economic growth. 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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE240100039
Funder
Australian Research Council
Funding Amount
$470,000.00
Summary
Advanced HR-ICP-MS facility for marine, Antarctic and environmental samples. This proposal seeks support for a shared High Resolution Inductively Coupled Plasma Mass Spectrometry facility for Tasmanian researchers. The existing UTAS instrument is approaching end-of-life and is becoming increasingly unreliable. Access to enhanced capabilities embodied in a rejuvenated facility, along with a renewed lifespan, is essential for continued analysis of ultra-trace elements and isotopes in challenging s ....Advanced HR-ICP-MS facility for marine, Antarctic and environmental samples. This proposal seeks support for a shared High Resolution Inductively Coupled Plasma Mass Spectrometry facility for Tasmanian researchers. The existing UTAS instrument is approaching end-of-life and is becoming increasingly unreliable. Access to enhanced capabilities embodied in a rejuvenated facility, along with a renewed lifespan, is essential for continued analysis of ultra-trace elements and isotopes in challenging samples from southern environments. The new instrument will allow TAS researchers and their (inter)national collaborators to undertake world-leading research, enhancing competitive profiles in a diverse range of research areas (oceanography, analytical chemistry, Antarctic studies, environmental assessment, geochemistry). Read moreRead less