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Mitochondrial inner membrane architecture in skeletal muscle pathophysiology

骨骼肌病理生理学中的线粒体内膜结构

基本信息

批准号：
10657388
负责人：
Bingwei Lu
金额：
$ 34.43万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-17 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10657388
关键词：
ATP phosphohydrolase Aging Amyotrophic Lateral Sclerosis Animals Apoptosis Architecture Binding Biochemical Bioenergetics Biological Biology Buffers C9ALS C9ORF72 Calcium Cell division Cell physiology Cells Complex Crista ampullaris Cytosol Degenerative Disorder Denervation Development Dipeptides Disease Drosophila genus Functional disorder Genetic Genetic Models Genetic Screening Goals Health Inner mitochondrial membrane Link Maintenance Medicine Membrane Membrane Structure and Function Metabolism Mitochondria Mitochondrial Encephalomyopathies Mitochondrial Myopathies Modeling Molecular Molecular Genetics Molecular Target Motion Motor Neuron Disease Muscle Muscle Development Muscle Mitochondria Muscle function Myopathy Neuromuscular Junction Notch Signaling Pathway Numbness Organelles Outer Mitochondrial Membrane PINK1 gene Parkin Pathogenesis Pathology Pathway interactions Peptide Hydrolases Play Process Proteins Proteomics Quality Control Regulation Ribosomes Role Signal Pathway Signal Transduction Site Skeletal Muscle Structure Synapses System Tissues Toxic effect Translations age related age related neurodegeneration experimental study fly gene product insight mitochondrial dysfunction model organism muscle degeneration muscle form muscular structure neuromuscular normal aging notch protein novel novel therapeutics proteostasis restraint sarcopenia skeletal muscle wasting stem cells tool

项目摘要

Project Summary Muscle is a contractile tissue that generates forces and motions vital for animal survival. The molecular and cellular mechanisms governing its structural and functional integrity are not well understood. Selective dysfunction and degeneration of neuromuscular tissues have been observed in disease conditions featuring mitochondrial abnormality, emphasizing the particular importance of mitochondria to the functionality and integrity of muscle tissues. Mitochondria play important roles in cellular bioenergetics as well as other essential aspects of cellular physiology. The mitochondrial processes that are essential for the structural and functional integrity of skeletal muscle, and how these processes are regulated in health and disease are poorly defined. It is becoming increasingly clear that fundamental mechanisms underlying the development, function, and maintenance of skeletal muscle are conserved across metazoans. Thus genetic model organisms are poised to make significant contributions to our understanding of these mechanisms. In our previous studies, we have used Drosophila as a model to demonstrate the importance of Numb/Notch signaling and asymmetric progenitor cell division during muscle development, and PINK1/Parkin-directed mitochondrial quality control in skeletal muscle maintenance. We have also used the fly neuromuscular junction (NMJ) as a model to dissect synaptic mechanisms involved in age- related neurodegenerative diseases. In our most recent studies, we have found that protein quality control in the mitochondrial intermembrane space (IMS) is important for skeletal muscle function and maintenance. We found that dipeptide repeats (DPRs) derived from unconventional translation of the GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) called c9ALS, disrupt mitochondrial function by altering IMS proteostasis and inner membrane (IM) architecture. Our genetic modifier screens identified a number of signaling pathways in mitigating this ALS-related muscle pathology. The goal of this proposal is to use proteomic, molecular genetic, and cell biological tools to define the mechanism of action of the identified genetic pathways, in an effort to achieve a holistic view of the regulation and function of mitochondrial IM architecture in skeletal muscle function and maintenance. Two Specific Aims will help us reach this goal. In Aim 1, we will examine the molecular mechanisms of how c9ALS disease gene product disrupts muscle mitochondrial IMS/IM structure and function. Novel genetic tools will be used to perform ultrastructural studies and find the interactome of DPR within these structures. In Aim 2, we will delineate the cellular quality control mechanisms that maintain IMS/IM integrity by restraining the synthesis or promoting the metabolism of DPR. The role of these quality control mechanisms in maintaining mitochondrial and skeletal muscle structure and function during normal aging will also be examined. These studies will significantly advance our understanding of the role of mitochondria in maintaining skeletal muscle structure and function. Results from this study promise to inform the development of novel and rational muscle-targeting medicine for ALS and conditions such as sarcopenia.