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

骨骼肌、心脏和大脑都是需要高能量的组织， 线粒体功能障碍最近，一种影响线粒体的新型遗传疾病已经被发现， 与线粒体蛋白CHCHD10（D10）的突变有关，其功能是 仍然大部分未知。突变体D10导致严重的常染色体显性线粒体疾病， 具有不同的表型特征，从肌病到运动神经元疾病， 额颞叶痴呆我们先前表明，在线粒体中，D10形成二聚体， 与其副产物蛋白CHCHD2（D2）复合。有趣的是，D2的突变也与 家族性神经退行性疾病研究其临床表现和发病机制 突变体D10在体内，我们已经产生了一个敲在小鼠窝藏的第一个致病性D10 在人类中报告的突变（S59L，对应于小鼠S55L）。在D10 S55 L小鼠肌肉中 和心脏线粒体，D10和D2积累和聚集，导致线粒体 功能障碍和退化。这些异常导致了一个深刻的整合线粒体 应激反应（ISRmt），改变转录谱和代谢，并最终导致 致命的心肌病相反，D10敲除小鼠不表现mtISR， 表型正常，表明D10S55L通过毒性机制引起疾病， 而不是功能丧失。在本应用中，我们将研究D10和D2的正常功能以及 D10S55L小鼠线粒体改变的潜在机制。由于D10突变导致 我们还将研究神经系统在人类神经退行性疾病中的参与， D10S55L小鼠。然后，我们将确定代谢和分子生物标志物，以帮助监测疾病 当然了最后，我们将测试ISRmt在D10S55L小鼠中的药理学调节作用， 一种治疗策略该项目的影响将是促进合理的方法， D10突变患者的疾病发病机制，这可以扩展到其他 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