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，它们受到线粒体的严重影响。 功能障碍最近，一种影响线粒体的新型遗传疾病与 线粒体蛋白CHCHD10（D10）的突变，其功能在很大程度上仍然未知。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， 肌病和心肌病到运动神经元疾病和额颞叶痴呆。父R01， 与多样性补充申请相关的研究D10的正常功能和机制 D10 S55L突变小鼠中潜在的线粒体改变。该补编将支持林女士的工作。 Nneka Southwell是Manfredi博士小组神经科学项目的研究生。的重点 补充中提出的研究是关于涉及1C代谢和核苷酸的代谢重新布线 她在D10 S55L突变小鼠中观察到的不平衡，从最受影响的组织开始， 心脏，但也探索不同大脑区域的代谢变化。后者具有很强的创新性，因为 关于CNS中线粒体代谢应激反应知之甚少， 心脏和其他组织共享这些通路，而其他通路可能完全不同。代谢适应不良 重连是一个新兴的和迷人的领域，它具有令人兴奋的承诺，提供新的疾病生物标志物 和治疗靶点，不仅用于这种线粒体疾病，而且用于许多其他疾病， 代谢适应机制为这一多样性补充提出的研究将提供充足的 Southwell女士有机会成为代谢和疾病方面的专家，这是一个研究领域， 在生物医学领域获得了巨大的动力，因为代谢失调的作用越来越多， 与多种疾病有关。她将积累的知识和技术技能 从事这个项目将使她能够很好地发展她的独立，尖端的研究 代谢紊乱在退行性疾病中的作用。

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 and cardiomyopathy to motor neuron disease and frontotemporal dementia. The parent R01 that is linked to this application for Diversity Supplement investigates the normal function of D10 and the mechanisms underlying mitochondrial alterations in D10 S55L mutant mice. The supplement will support the work of Ms. Nneka Southwell, a graduate student in the Neuroscience Program in Dr. Manfredi’s group. The focus of the studies proposed in the supplement is on the metabolic rewiring involving 1C metabolism and nucleotide imbalance, which she has observed in the D10 S55L mutant mouse, starting from the most affected tissue, the heart, but also exploring metabolic alterations in various brain regions. The latter is highly innovative because very little is known about mitochondrial metabolic stress responses in the CNS and it is possible that some pathways are shared with heart and other tissues, while other could differ entirely. Maladaptive metabolic rewiring is an emerging and fascinating field, which holds exciting promise to provide novel disease biomarkers and therapeutic targets, not only for this mitochondrial disorder, but also for many other diseases that share metabolic adaptation mechanisms. The studies proposed for this Diversity Supplement will provide ample opportunities for Ms. Southwell to become an expert in metabolism and disease, an area of research that is gaining tremendous momentum in the biomedical space, as a role for metabolic dysregulation is increasingly being linked to a broad spectrum of diseases. The knowledge and technical skills that she will accumulate working on this project will position her well to being able to develop her independent, cutting-edge research on the role of metabolic dysfunction in degenerative diseases.