Fission, Fusion And Distribution Of Mitochondria In Mammalian Cells
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
Mitochondria are small cellular compartments that produce most of the cell's energy in the form of ATP. Mitochondria were once thought of as small bean-shaped organelles floating around in the cell, however it has become clear that this is not the case. Mitochondria are found as a network of tubules radiating from around the nucleus and they undergo constant changes in their shape through both fission and fusion events. Mitochondria are transported along microtubules which act as highways in the ....Mitochondria are small cellular compartments that produce most of the cell's energy in the form of ATP. Mitochondria were once thought of as small bean-shaped organelles floating around in the cell, however it has become clear that this is not the case. Mitochondria are found as a network of tubules radiating from around the nucleus and they undergo constant changes in their shape through both fission and fusion events. Mitochondria are transported along microtubules which act as highways in the cell so that they can be distributed to areas that require ATP or other functions particular to mitochondria such as their ability to regulate the release of calcium. In specialist cells, mitochondria are organised even further. Sperm cells contain mitochondria packed around the mid-piece of the flagellum so that ATP can be utilised directly for swimming. Mitochondria are also highly organised in muscle cells to supply ATP for movement while in pancreatic cells mitochondria at the cell's edge help to regulate the secretion of molecules such as insulin into the bloodstream. While we are beginning to understand the great importance of mitochondria to the cell, we are yet to work out how these organelles undergo the drastic morphological changes which are essential for cellular function. In this application, we plan to identify and characterise the proteins involved in the division of mitochodria and the movement of these organelles along the microtubule highways. Understanding the basic mechanisms of mitochondrial dynamics in tissue culture cells will provide valuable insights into mitochondrial segregation and specialisation in differentiated cells such as sperm, nerve, muscle and pancreatic cells, where such events are crucial for function.Read moreRead less
Biogenesis Of Respiratory Chain Complex I And Analysis Of Assembly Defects In Patients With Mitochondrial Disease
Funder
National Health and Medical Research Council
Funding Amount
$254,250.00
Summary
Complex I of the mitochondrial respiratory chain is a large assembly of protein subunits that is involved in the main production of cellular energy. Complex I is found in intracellular compartments termed mitochondria. The predicament for Complex I is that in order for it to be built, it requires 38 different proteins that are made in one place in the cell to be imported into mitochondria and then somehow joined together with the 7 other subunits that are made by mitochondria. This is clearly a ....Complex I of the mitochondrial respiratory chain is a large assembly of protein subunits that is involved in the main production of cellular energy. Complex I is found in intracellular compartments termed mitochondria. The predicament for Complex I is that in order for it to be built, it requires 38 different proteins that are made in one place in the cell to be imported into mitochondria and then somehow joined together with the 7 other subunits that are made by mitochondria. This is clearly a complicated procedure and we have little information on how its assembly is achieved. We do know however that mistakes in the assembly of Complex I do happen. In Australia, about 50 children born each year have inherited disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others present later causing a range of degenerative diseases, particularly affecting brain, muscle and heart. The most common defect in these patients is a loss in the activity of Complex I. Interestingly it seems that in most cases, the defect is not due to a mutation in one or more of the Complex I subunits and so we believe that such defects arise form accessory proteins that are involved in the construction of Complex I. The aim of this proposal is to investigate how Complex I is assembled and to identify and characterise accessory proteins. We will also analyse assembly defects by studying skin fibroblasts from patients. This work will aid in our understanding of not only how protein complexes are built, but how defects in their assembly can cause disease. This will not only be informative to families of affected individuals but may aid in future diagnosis and prevention of mitochondrial disease.Read moreRead less
Neurologic Effects Of Mutational Load In MELAS Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$505,786.00
Summary
This project will use a new stem cell model to discover what happens to brain cells in patients with the MELAS 3243A>G mutation, a common genetic mutation found in 1-500 Australians. Brain cells will be grown from our stem cell model and used to find out how this mutation causes problems in the affected brain cells. We will find out what happens to the brain when the amount of mutation is reduced in vitro. By understanding what happens, we will be able to design new treatments for this disord ....This project will use a new stem cell model to discover what happens to brain cells in patients with the MELAS 3243A>G mutation, a common genetic mutation found in 1-500 Australians. Brain cells will be grown from our stem cell model and used to find out how this mutation causes problems in the affected brain cells. We will find out what happens to the brain when the amount of mutation is reduced in vitro. By understanding what happens, we will be able to design new treatments for this disorder.Read moreRead less
Evaluation Of Pathogenic Mechanisms Involved In Nuclear And Mitochondrial DNA-encoded Mitochondrial Disorders
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Mitochondria produce energy for the cell. Disorders of mitochondrial function can cause human disease. These diseases are referred to as the mitochondrial disorders. Mitochondrial disorders usually involve multiple tissues, particularly the muscle and brain.These disorders are usually caused by mutations in two different types of DNA; nuclear and mitochondrial DNA. There are many forms of mitochondrial disorders; some affect young children or infants and others cause adult disease. In some cases ....Mitochondria produce energy for the cell. Disorders of mitochondrial function can cause human disease. These diseases are referred to as the mitochondrial disorders. Mitochondrial disorders usually involve multiple tissues, particularly the muscle and brain.These disorders are usually caused by mutations in two different types of DNA; nuclear and mitochondrial DNA. There are many forms of mitochondrial disorders; some affect young children or infants and others cause adult disease. In some cases, genetic defects may cause the same disease and other mutations may cause a wide range of symptoms. The reason why this occurs is unknown. This study investigates several factors that may determine why some mutations lead to a certain disease and why others may cause different diseases. These factors include the variation in energy levels that are produced by the mutant cells, and the different levels of vunerability that mutated cells may have to induced cell death. The goal of this proposal is to identify the factors that lead to mutations causing different clinical symptoms with the overall aim being to design treatment for these chronic diseases.Read moreRead less
Mitochondrial Ribosomal Pentatricopeptide Domain Proteins Regulate Protein Synthesis In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$444,108.00
Summary
Mitochondria in our cells regulate energy production from food and play an important role in health and disease. Defects in mitochondrial protein synthesis lead to severe neurodegenerative and sensory diseases and may contribute to cancer and ageing. This research aims to investigate the role of mitochondrial proteins that regulate translation in mitochondrial diseases. Characterisation of these proteins provides an unexplored resource of potential disease modulators and drug targets.
Regulation Of Gene Expression In Mitochondrial Disease
Funder
National Health and Medical Research Council
Funding Amount
$338,362.00
Summary
Mitochondrial diseases affect 4000 children every year and most of these children do not reach adulthood. These diseases result from defects in mitochondria, energy producing compartments within cells. We have discovered a protein that controls mitochondrial gene expression and used it to rescue dysfunction in cells from patients with mitochondrial disease. We will determine its function and role in cell health, allowing us to evaluate its importance in mitochondrial disease.
Defining The Genomic Basis Of Mitochondrial Complex I Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$639,682.00
Summary
The human genome project led to new technologies that will revolutionise genetic testing. Previously, we could only sequence genes one at a time. Next Generation sequencing allows analysis of hundreds or thousands of genes simultaneously. We will analyse 90 genes in 100 children with severe disorders of mitochondrial energy generation. This will provide proof of principle for the introduction of this technology into routine medical testing and identify new genes causing these diseases.
The Role Of Mitochondrial DNA In Age-related Hearing Loss
Funder
National Health and Medical Research Council
Funding Amount
$260,475.00
Summary
Hearing loss is an extremely common and under-studied age-related disability, affecting 39% of Australians aged 50 years or older. Both genetic and environmental factors may contribute to the development of age-related hearing loss. Human genetic material (DNA) resides in two places in body cells; the nucleus and in organelles called mitochondria. This is due to the fact that mitochondria were derived from bacteria that were engulfed by the cell back in primordial life. Although this genetic mat ....Hearing loss is an extremely common and under-studied age-related disability, affecting 39% of Australians aged 50 years or older. Both genetic and environmental factors may contribute to the development of age-related hearing loss. Human genetic material (DNA) resides in two places in body cells; the nucleus and in organelles called mitochondria. This is due to the fact that mitochondria were derived from bacteria that were engulfed by the cell back in primordial life. Although this genetic material is different to nuclear DNA, it has an essential role in helping to provide energy for the cell. Genetic mutations in the DNA residing in the mitochondria have been associated with a number of conditions, usually affecting tissues that require large amounts of energy, such as the brain, muscle, heart, retina and the cochlea of the ear. The commonest clinical manifestation of mitochondrial disease is thought to be hearing loss. This project investigates the role that abnormal mitochondrial DNA plays in the development of hearing impairment by studying subjects from a representative Australian community who participated in a large population study of hearing loss. We will assess whether different sectors of mitochondrial DNA predispose particular individuals to the development of hearing loss or accelerate its onset. The Blue Mountains Hearing Study is able to take into account other factors known to be associated with hearing loss (industrial noise exposure, diabetes, smoking).Read moreRead less
Genetic Variation Of Mitochondrial Complex I: Its Role In Rare And Common Diseases
Funder
National Health and Medical Research Council
Funding Amount
$628,415.00
Summary
Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the uniqu ....Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the unique mitochondrial DNA we inherit only from our mothers. Many more genes await discovery. This grant focuses on the most common energy generation disorder, known as Complex I deficiency. Complex I requires 46 separate components to be assembled together in order to work properly, but mutations in the 46 genes encoding these components only seem to explain disease in about half of all patients. Our aim is to identify new disease genes and to determine whether some patients have mutations in two different genes that interact to cause disease, rather than in a single gene. We will use a number of methods to pinpoint where in the genome the causative genes are located and then home in on the exact changes in the genes that cause disease. Identifying these genes will allow us to improve future diagnosis and prevention of mitochondrial disease. We will also generate mice in which one of the Complex I genes has been knocked out. These mice will allow us to better understand the basic disease mechanisms that link gene changes to disease. Understanding the basic biology may allow us to develop new methods of treatment. The mouse models will also be useful for trialling new treatments and for investigating the role of milder mitochondrial problems in common diseases such as diabetes and Parkinson disease. Any new treatments could potentially have wide application.Read moreRead less