The role of the mitochondrial protein dimer CHCHD2/10 in health and disease

骨骼肌、心脏和大脑是需要高能量的组织，受到严重的 线粒体功能障碍。最近，一种影响线粒体的新形式的遗传病 与线粒体蛋白CHCHD10(D10)的突变有关，其功能是 这在很大程度上仍然是未知的。突变D10导致严重的常染色体显性遗传性线粒体疾病， 有不同的表型特征，从肌病到运动神经元疾病和 额颞部痴呆。我们之前发现，在线粒体中，D10以二聚体的形式存在 与其伴生蛋白CHCHD2(D2)的复合体。有趣的是，D2基因的突变也与 患有家族性神经退行性疾病。研究其临床表现和发病机制 体内突变的D10，我们已经在携带第一个致病D10的小鼠中产生了敲击 在人类中发现的突变(S59L，对应于小鼠的S55L)。在D10S55L小鼠肌肉中 而心脏线粒体、D10和D2积累和聚集，导致线粒体 功能障碍和退化。这些异常导致了线粒体的深度整合。 应激反应(ISRmt)，改变转录谱和新陈代谢，最终导致 死于致命的心肌病。相反，D10基因敲除小鼠不会表现出mtISR，而是 表型正常，提示D10S55L通过毒性机制和 而不是丧失功能。在这个应用中，我们将研究D10和D2的正规函数以及 D10S55L小鼠线粒体改变的机制。因为D10突变会导致 ，我们还将研究神经系统在 D10S55L小鼠。然后我们将确定代谢和分子生物标记物，以帮助监测疾病 当然了。最后，我们将检测ISRmt对D10S55L小鼠AS的药理调节作用。 一种治疗策略。该项目的影响将是促进合理的方法来实现目标 D10突变患者的疾病发病机制，这可能扩展到其他 ISRmt介导的线粒体疾病

Skeletal muscle, heart, and brain are high-energy requiring tissues that are severely affected by mitochondrial dysfunction. Recently a novel form of genetic disease affecting mitochondria has been associated with mutations in a mitochondrial protein, CHCHD10 (D10), whose function is still largely unknown. Mutant D10 causes severe autosomal dominant mitochondrial diseases, with diverse phenotypic features, ranging from myopathy to motor neuron disease and frontotemporal dementia. We previously showed that in mitochondria D10 forms a dimeric complex with its paralog protein, CHCHD2 (D2). Interestingly, mutations in D2 are also associated with familial neurodegenerative diseases. To study the manifestations and disease mechanisms of mutant D10 in vivo, we have generated a knock in mouse harboring the first pathogenic D10 mutation reported in humans (S59L, corresponding to mouse S55L). In D10S55L mouse muscle and heart mitochondria, D10 and D2 accumulate and aggregate, leading to mitochondrial dysfunction and degeneration. These abnormalities result in a profound integrated mitochondrial stress response (ISRmt), altering transcriptional profiles and metabolism, and ultimately resulting in fatal cardiomyopathy. Conversely, D10 knock out mice do not manifest mtISR and are phenotypically normal, suggesting that D10S55L causes disease through a toxic mechanism and not a loss of function. In this application, we will study the normal function of D10 and D2 and the mechanisms underlying mitochondrial alterations in D10S55L mice. Since D10 mutations cause neurodegeneration in humans, we will also investigate the involvement of the nervous system in D10S55L mice. We will then identify metabolic and molecular biomarkers to help monitor disease course. Lastly, we will test the effects of pharmacological modulation of ISRmt in D10S55L mice as a therapeutic strategy. The impact of this project will be to facilitate rationale approaches to target disease pathogenesis in patients with D10 mutations, which could be extended to other mitochondrial diseases mediated by ISRmt