MitoCluster: an integrated phenotyping and mouse model generation platform for mitochondrial disease and dysfunction.

线粒体是人体细胞内大量存在的微小能量发生器（100 -1000个）。原发性线粒体疾病（PMDs）是一大类遗传性疾病，损害线粒体和人体制造能量的能力。它们会导致致残症状，严重影响生活质量。虽然个体罕见，但作为一个群体，pmd是神经系统疾病的常见原因。遗传疾病是由我们的遗传密码（DNA）的改变引起的，DNA携带着制造蛋白质的指令，蛋白质是生命的基石。PMDs是由细胞核内的DNA或线粒体内的少量DNA （mtDNA）的改变引起的。经前综合症可在出生、童年或成年时引起症状，并根据受影响最严重的身体部位引起各种各样的医疗问题。由于线粒体几乎存在于所有细胞中，因此身体的任何系统都可能受到影响，患者可能会出现耳聋、失明、心脏病、癫痫、糖尿病和肠道问题等。肌肉特别容易受到能量减少的影响，从而导致疲劳和虚弱。不幸的是，目前还没有针对经前综合症的有效治疗方法。重要的是，在PMDs中看到的线粒体缺陷的影响也存在于其他常见疾病（遗传性和非遗传性）中，如痴呆、糖尿病和癌症。因此，更好地理解pmd也可以帮助我们理解这些更常见的情况。PMD研究以及线粒体参与的其他疾病的一个障碍是缺乏相关的小鼠模型。因此，开发良好的小鼠模型是线粒体研究界的主要目标。在小鼠身上重建PMD将使研究人员能够确认基因突变导致PMD症状，找到随时间推移测量疾病的新方法，并开发和测试新的治疗方法，然后可以更安全地进行人体试验。在小鼠体内建立人类PMDs的mtDNA模型非常具有挑战性（因为很难改变线粒体内的少量DNA）。然而，最近已经建立了改变mtDNA的新工具。此外，测量小鼠发育、运动和行为的现代技术可以在不给小鼠施加压力的情况下长期应用，这将使研究人员能够更准确、更人道地研究这些动物的pmd。MitoCluster是一个由英国和意大利的研究人员组成的网络，他们将开发新的pmd小鼠模型，并应用先进的技术来评估这些模型和现有的小鼠模型，以：(1)提供pmd的新见解、治疗方法和生物指标（生物标志物）；(2)有助于了解线粒体在其他常见疾病（如痴呆、糖尿病和癌症）中的作用。我们的团队由拥有线粒体功能和遗传学、经前症候群和临床试验专业知识的医生和科学家组成。我们将与对开发PMDs疗法有强烈兴趣的制药公司密切合作，并首先在小鼠身上进行研究，帮助确定最有可能使患者受益的治疗方法，并与其他与线粒体缺陷相关的疾病的研究人员密切合作，以确保我们对这些疾病的了解取得进展。最后，我们将定期与受PMD影响的患者和护理人员以及倡导团体会面，以确保我们解决对更广泛的PMD社区重要的问题。我们的团队致力于动物研究的“3r”原则。我们将通过将收集的所有数据/样本用于多次测试、与其他研究人员共享发现以及用细胞系或果蝇代替小鼠进行早期研究来减少使用的小鼠数量。我们将改进目前测量小鼠线粒体的方法，使其压力更小，更准确，更可复制，并与人类更相关。

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.