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: LE0989197
Funder
Australian Research Council
Funding Amount
$225,000.00
Summary
Reaction Kinetics Analysis Facility. This proposal will establish a world-class resource to support major research efforts in a wide range of applications associated with the study of reaction mechanisms and intermediates in systems ranging from small molecules to complex polymers. This facility, which is unique in Australia and strongly builds on the broad expertise of the involved researchers at the participating institutions, will address an important need in the areas of physical-organic and ....Reaction Kinetics Analysis Facility. This proposal will establish a world-class resource to support major research efforts in a wide range of applications associated with the study of reaction mechanisms and intermediates in systems ranging from small molecules to complex polymers. This facility, which is unique in Australia and strongly builds on the broad expertise of the involved researchers at the participating institutions, will address an important need in the areas of physical-organic and physical chemistry by strengthening our capacity for cutting-edge research in reactive intermediate chemistry. The Facility will help to establish frontier technologies in the chemical sciences for building and transforming Australian industries in line with national research priorities.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100177
Funder
Australian Research Council
Funding Amount
$300,000.00
Summary
Advanced electron paramagnetic resonance (EPR) facilities for chemical, biological and materials sciences. New instrumentation to advance national research in hydrogen fuel generation from renewable sources, new generation photo-voltaic technologies, novel polymer and other chemical materials and advanced computing systems will be provided by this project. A new high sensitivity electron paramagnetic resonance facility, located at the Australian National University, will serve researchers in the ....Advanced electron paramagnetic resonance (EPR) facilities for chemical, biological and materials sciences. New instrumentation to advance national research in hydrogen fuel generation from renewable sources, new generation photo-voltaic technologies, novel polymer and other chemical materials and advanced computing systems will be provided by this project. A new high sensitivity electron paramagnetic resonance facility, located at the Australian National University, will serve researchers in the ACT region devoted to the broad range of activities summarised above. A particular focus involves novel, biologically inspired energy systems and high efficiency solar cell technology.Read moreRead less
Reaction transition states of halide-cluster complexes via velocity-map imaging of photoelectrons. This study will investigate the transition point between the reactants and products of a chemical reaction using a novel photoelectron imaging technique, velocity-map imaging. It is this region of chemical reactions that is the least understood. By combining the use of weakly bound negatively charged clusters and laser photodetachment of these clusters, information can be gleaned about these transi ....Reaction transition states of halide-cluster complexes via velocity-map imaging of photoelectrons. This study will investigate the transition point between the reactants and products of a chemical reaction using a novel photoelectron imaging technique, velocity-map imaging. It is this region of chemical reactions that is the least understood. By combining the use of weakly bound negatively charged clusters and laser photodetachment of these clusters, information can be gleaned about these transition states. The technique will be applied to an important class of halide-cluster complexes that form a set of prototypical reactions. These species also play important roles ranging from ozone depletion through to industrial chemistry.Read moreRead less
Imaging chemical reaction dynamics from the transition state to reaction products. Chemical reactions play a key role in many atmospheric, environmental and industrial processes. An understanding of reactions at the molecular level will lead to significant economic benefits, through more efficient reaction control, and through the identification of the key environmental factors which influence why particular reactions proceed. Our study of chemical reaction dynamics has been driven by technolo ....Imaging chemical reaction dynamics from the transition state to reaction products. Chemical reactions play a key role in many atmospheric, environmental and industrial processes. An understanding of reactions at the molecular level will lead to significant economic benefits, through more efficient reaction control, and through the identification of the key environmental factors which influence why particular reactions proceed. Our study of chemical reaction dynamics has been driven by technological advances which enable key stages of a reaction to be imaged and studied at the molecular level. Read moreRead less
A Midas touch for electrophiles in new reaction development. This project aims to address the lack of knowledge about how high-value organic molecules are formed in gold-catalysed reactions by advancing a novel mode of catalysis. This project expects to generate new knowledge about these gold-catalysed reactions using an innovative, interdisciplinary approach incorporating computational and synthetic techniques. Expected outcomes of this project include the optimisation and development of import ....A Midas touch for electrophiles in new reaction development. This project aims to address the lack of knowledge about how high-value organic molecules are formed in gold-catalysed reactions by advancing a novel mode of catalysis. This project expects to generate new knowledge about these gold-catalysed reactions using an innovative, interdisciplinary approach incorporating computational and synthetic techniques. Expected outcomes of this project include the optimisation and development of important organic reactions and enhancing collaboration nationally and internationally between computational and synthetic chemists. This should provide significant benefits in the form of improved chemical reactions for chemists to prepare new pharmaceuticals, agrochemicals and materials.Read moreRead less
Hydrogen Abstraction in Chemical, Biochemical and Polymerization Processes. Hydrogen-abstraction reactions are of vital importance in the chemical, biochemical and polymerization processes that occur in everyday life. The objective of the proposed research is to improve our understanding of such reactions. State-of-the-art quantum chemistry calculations will be used to examine a broad range of hydrogen-abstraction reactions, and to obtain accurate information about the factors that influence suc ....Hydrogen Abstraction in Chemical, Biochemical and Polymerization Processes. Hydrogen-abstraction reactions are of vital importance in the chemical, biochemical and polymerization processes that occur in everyday life. The objective of the proposed research is to improve our understanding of such reactions. State-of-the-art quantum chemistry calculations will be used to examine a broad range of hydrogen-abstraction reactions, and to obtain accurate information about the factors that influence such reactions. Building on this work, more detailed case studies will be performed in two important areas: the hydrogen-abstraction steps in biochemical reactions mediated by coenzyme B12, and chain-transfer processes in conventional and controlled free-radical polymerization.Read moreRead less
Switchable and stereocontrolled photoredox catalysis. This project aims to develop new catalytic synthetic reactions for the rapid and more direct functionalisation of organic compounds under mild conditions with the use of visible light. An integrated experimental and computational approach will be used to design potent visible-light photocatalysts that retain the advantages of standard photoredox catalysis but with the added ability to intercept and, thus control, reactive intermediates in sit ....Switchable and stereocontrolled photoredox catalysis. This project aims to develop new catalytic synthetic reactions for the rapid and more direct functionalisation of organic compounds under mild conditions with the use of visible light. An integrated experimental and computational approach will be used to design potent visible-light photocatalysts that retain the advantages of standard photoredox catalysis but with the added ability to intercept and, thus control, reactive intermediates in situ. This will enable the control of stereochemistry in photoredox reactions – not possible with standard catalysts - and establish other useful synthetic transformations. These strategies will make it easier to prepare valuable classes of organic molecules – efficiently, safely, and cost-effectively.
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