Mitochondrial diseases leave patients with disabling fatigue, weakness, and organ damage because their cells cannot generate enough energy, yet no effective treatments exist. These rare genetic disorders—caused by mutations in either nuclear or mitochondrial DNA—affect muscles, brain, heart, and gut, and can appear at any age. A major barrier to developing therapies is the lack of good mouse models, especially for mutations in mitochondrial DNA itself. MitoCluster brings together UK and Italian researchers to create new mouse models of primary mitochondrial diseases using recently developed tools to edit mitochondrial DNA. They will also apply advanced, low-stress techniques to track disease progression in these animals over time. If successful, the project will deliver validated mouse models, biological markers, and candidate therapies that can move into human trials. Because faulty mitochondria also play a role in common diseases such as dementia, diabetes, and cancer, insights from these models could extend beyond rare mitochondrial disorders. The team will work with drug companies and patient groups to ensure the research addresses real clinical priorities.
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Mitochondria are tiny energy generators that exist in large numbers (100s-1000s) inside human cells. Primary mitochondrial diseases (PMDs) are a large group of genetic disorders that impair mitochondria and the body's ability to make energy. They can cause disabling symptoms that may impact very severely on quality of life. Though individually rare, as a group PMDs are a common cause of nervous system diseases. Inherited disorders are caused by alterations in our genetic code (DNA) that carries the instructions for making proteins, the building blocks of life. PMDs are caused by alterations in DNA inside the cell nucleus or a small amount of DNA (mtDNA) inside the mitochondria themselves. PMDs can cause symptoms at birth, in childhood or during adulthood, and cause a wide variety of medical problems, depending on the body parts most severely affected. As mitochondria are present in almost all cells, any system in the body can be affected and patients can develop deafness, blindness, heart problems, seizures, diabetes and gut problems among others. Muscles are particularly susceptible to reduced energy, which causes fatigue and weakness. Unfortunately, there are currently no effective treatments for PMDs. Importantly, the effects of faulty mitochondria seen in PMDs are also present in other common diseases (genetic and non-genetic), such as dementia, diabetes and cancer. Consequently, a better understanding of PMDs could also help us to understand these more common conditions. A barrier to PMD research, and other diseases in which mitochondria play a role, is a lack of relevant mouse models. Consequently, developing good mouse models is a major goal of the mitochondrial research community. Recreating PMDs in mice will allow researchers to confirm that genetic mutations cause PMD symptoms, find new ways to measure the disease over time and develop and test new treatments that can then more safely progress to trials in humans. It has been very challenging to create mtDNA models of human PMDs in mice (as it is difficult to alter the small amounts of DNA that sit inside mitochondria). However, new tools to change mtDNA have recently been established. Also, modern techniques to measure mouse development, movement and behaviour that can be applied over long periods without stressing mice will allow researchers to study PMDs in these animals more accurately and humanely. MitoCluster is a network of researchers based in the UK and Italy who will develop new mouse models of PMDs and apply advanced techniques to evaluate these and existing mouse models, to: (1) deliver new insights, therapies and biological indicators (biomarkers) of PMDs; and (2) help understand the role of mitochondria in other common diseases (e.g., dementia, diabetes and cancer). Our team combines doctors and scientists who have expert knowledge of mitochondrial function and genetics, PMDs and clinical trials. We will work closely with drug companies with strong interest in developing therapies for PMDs and help prioritise the treatments most likely to benefit patients by studying them in mice first, and link closely with researchers of other disorders linked with faulty mitochondria, to ensure the knowledge we generate advances understanding in these diseases. Finally, we will meet regularly with patients and carers affected by PMDs and advocacy groups, to ensure we address questions that are important to the wider PMD community. Our group is committed to "3Rs" principles for animal research. We will reduce the number of mice used by using all data/samples collected for multiple tests, by sharing findings with other researchers and by replacing mice with cell lines or flies for early research. We will refine current methods to measure mitochondria in mice to make them less stressful, more accurate and reproducible, and more relevant to humans.
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