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
EXAMINING THE RELATIONSHIP BETWEEN MATRIPTASE-2 AND HEMOJUVELIN, TWO ESSENTIAL REGULATORS OF IRON HOMEOSTASIS
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
The control of iron levels is important in health and well being. Too little can lead to iron deficiency and anaemia, conversly too much can lead to haemochromatosis and tissue damage. We will examine the role of two proteins, matriptase-2 and hemojuvelin that when mutated cause iron deficiency or iron overload respectively. We will study how these proteins interact and work in opposite directions to control iron levels. The results will help to develop new therapeutics for iron disorders.
Iron is essential for brain health. Too little iron can cause problems with memory, concentration and attention and can result in below average intellectual performance or even stroke in children. Too much iron can also be harmful. In the iron overload disease haemochromatosis, iron deposition throughout the body can lead to organ damage in the liver and other tissues. Concentrations of iron in the brain can equal those in liver. Yet surprisingly little is known about the effects of iron on the ....Iron is essential for brain health. Too little iron can cause problems with memory, concentration and attention and can result in below average intellectual performance or even stroke in children. Too much iron can also be harmful. In the iron overload disease haemochromatosis, iron deposition throughout the body can lead to organ damage in the liver and other tissues. Concentrations of iron in the brain can equal those in liver. Yet surprisingly little is known about the effects of iron on the adult human brain. Although the adult brain has traditionally been considered to be protected from the effects of high body iron by the blood-brain barrier, modern techniques show brain iron loading in patients with iron overload disorders or with various brain diseases such as Alzheimer's disease and Parkinson's disease. Several recent studies, including our own, have found associations between mutations in genes important in iron metabolism and brain diseases such as Alzheimer's disease. As many as 30% of Australians have abnormal iron levels (too high or too low) that are often undiagnosed and untreated. There is growing reason to believe these men and women are more likely to have memory problems as well as being at increased risk of brain diseases such as Alzheimer's disease. There is an urgent need for a large-scale study of the short-term and long-term effects of iron levels and related genetic factors on brain health and function. Residents of the Western Australian town of Busselton have participated in a set of health surveys since 1966. We have studied the iron status and related genetic factors in over 3,000 Busselton people. We now propose to perform tests of memory, attention, concentration and related brain activities on the older members of this community group. This will allow us to discover the effects of relevant gene factors, and short- and long-term iron status on memory and other brain functions and on Alzheimer's disease and related disorders.Read moreRead less
By the time a patient first presents with symptoms of Parkinson's disease at the clinic, a large proportion (60-70%) of the cells in a specific part of the brain have been destroyed. This degeneration progresses until, within a few years, most of the cells have died. This project investigates the mechanisms involved in the continued death of cells and a possible new therapy that interrupts the progression. If the aims of this proposal are met, the drug could rapidly go to clinical trial.
Mechanisms Of Intestinal Iron Absorption And Consequences Of Iron Supplementation During The Perinatal Period
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Iron intake is particularly high during pregnancy and in the newborn to meet the requirements of the growing fetus and neonate. While it is widely recommended that women take iron supplements at this time, too much iron may adversely affect pregnancy outcome. The aim of this study is to understand the factors controlling iron intake in the perinatal and the consequences of excess iron. This will provide the physiological information required to make rational decisions about iron supplementation.
Red Cell Disorders And The Regulation Of Iron Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
Iron is an essential nutrient, but it is also toxic when present in excess, so the amount of iron moving into and around the body must be tightly controlled. In this project we will investigate how this body iron movement is regulated, and in particular the role played by macrophages, the cells that clean up old red blood cells. An understanding of this process will be of great benefit in the analysis and treatment of important blood diseases and disorders of iron metabolism.