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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

基本信息

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
项目类别：
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

项目摘要

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、心脏和大脑是需要能量的组织，它们受到线粒体的严重影响

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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
作者：
通讯作者：

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
通讯作者：
Mai K Nguyen;Kevin McAvoy;Szu-Chi Liao;Z. Doric;Iris Lo;Huihui Li;G. Manfredi;Ken Nakamura-Ken-Nakamur