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

线粒体蛋白二聚体 CHCHD2/10 在健康和疾病中的作用

• 批准号: 10164492
• 负责人: Giovanni Manfredi
• 金额: $ 6.95万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164492
• 关键词: Affect; Area; Biological Markers; Brain; Brain region; Cardiomyopathies; Degenerative Disorder; Disease; Frontotemporal Dementia; Genetic Diseases; Health; Heart; Inherited; Knowledge; Link; Metabolic; Metabolic dysfunction; Metabolic stress; Metabolism; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Motor Neuron Disease; Mutant Strains Mice; Mutation; Myopathy; Neurosciences; Nucleotides; Parents; Pathogenesis; Pathway interactions; Phenotype; Positioning Attribute; Research; Role; Skeletal Muscle; Technical Expertise; Tissues; Training; Work; biological adaptation to stress; career development; dimer; fascinate; graduate student; innovation; mitochondrial dysfunction; mutant; novel; programs; therapeutic target

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.

骨骼肌，心脏和大脑是高能量的，需要严重影响线粒体的组织 功能障碍。最近，一种影响线粒体的遗传疾病的新形式与 线粒体蛋白CHCHD10（D10）中的突变，其功能在很大程度上未知。突变D10 引起严重的常染色体显性线粒体疾病，具有潜水员表型特征，从 运动神经元疾病和额颞痴呆的肌病和心肌病。父r01是 链接到该多样性补充申请的链接，研究了D10的正常功能和机制 D10 S55L突变小鼠中的线粒体改变。该补充剂将支持女士的工作。 Nneka Southwell，Manfredi博士小组神经科学计划的研究生。重点 补充剂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，从受影响最大的组织开始， 心脏，但也探索各个大脑区域的代谢改变。后者是高度创新的，因为 关于中枢神经系统中的线粒体代谢应力反应知之甚少，有些可能有些 途径与心脏和其他组织共享，而其他组织可能完全不同。适应性代谢不良 重新布线是一个新兴而有趣的领域，它具有令人兴奋的前途，可以提供新型疾病生物标志物 和治疗靶标，不仅针对这种线粒体疾病，而且针对许多其他共享的疾病 代谢适应机制。为这种多样性补充提出的研究将提供充足的 Southwell女士成为代谢和疾病专家的机会，这是一个研究领域 在生物医学空间中获得巨大的动力，作为代谢失调的作用越来越多 与广泛的疾病有关。她将积累的知识和技术技能 在这个项目上工作将使她很好地定位她的独立，尖端的研究 关于代谢功能障碍在退行性疾病中的作用。

项目成果

Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy.

• DOI: 10.1016/j.celrep.2022.110475
• 发表时间: 2022-03-08
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Sayles, Nicole M.;Southwell, Nneka;McAvoy, Kevin;Kim, Kihwan;Pesini, Alba;Anderson, Corey J.;Quinzii, Catarina;Cloonan, Suzanne;Kawamata, Hibiki;Manfredi, Giovanni
• 通讯作者: Manfredi, Giovanni

Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2.

• DOI: 10.1093/hmg/ddab329
• 发表时间: 2021-11
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Mai K Nguyen;Kevin McAvoy;Szu-Chi Liao;Z. Doric;Iris Lo;Huihui Li;G. Manfredi;Ken Nakamura-Ken-Nakamur

A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.

• DOI: 10.15252/emmm.202216951
• 发表时间: 2023-07-10
• 期刊: EMBO molecular medicine
• 影响因子: 11.1