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Novel mechanism of neural and muscular degeneration

神经和肌肉退化的新机制

基本信息

批准号：
10624824
负责人：
Xin Jie Chen
金额：
$ 42.51万
依托单位：
UPSTATE MEDICAL UNIVERSITY
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：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624824
关键词：
Address Adenine Nucleotide Translocase Affect Aging Amyotrophic Lateral Sclerosis Animals Area Autophagocytosis Behavioral Bioenergetics Cause of Death Cell Death Cell Death Induction Cells Central Nervous System Charge Child Chronic progressive external ophthalmoplegia Clinical Cytoprotection Cytosol Data Defect Degenerative Disorder Dementia Disease Equilibrium Experimental Models FRAP1 gene Frontotemporal Dementia Functional disorder Future Gene Expression Profile Genes Genetic Transcription Goals Heart Histologic Human Impairment Inner mitochondrial membrane Intervention Knock-in Mouse Late-Onset Disorder Lateral Maintenance Membrane Missense Mutation Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Proteins Modeling Molecular Mus Muscle Muscle Weakness Mutation Myopathy Names Neuromuscular Diseases Neurons Nuclear Nucleotides Oxidative Phosphorylation Oxidative Phosphorylation Deficiency Oxidative Stress Parkinson Disease Pathogenicity Pathology Pathway interactions Peripheral Nervous System Diseases Phenotype Play Protein Import Protein Isoforms Proteins Repression Research Respiration Role SLC25A4 gene Seizures Skeletal Muscle Spastic Paraplegia Spinocerebellar Ataxias Stress Suppressor-Effector T-Lymphocytes Surface Syndrome System Testing Ubiquitination Validation Variant Yeasts aged cerebral atrophy dominant genetic mutation hearing impairment insight mitochondrial dysfunction mouse model muscle form mutant neural neuromechanism neuromuscular novel posttranscriptional preference psychiatric symptom receptor success tool translocase ubiquitin-protein ligase young adult

项目摘要

Ant1 is the muscle/heart/central nervous system (CNS) isoform of adenine nucleotide translocase that is primarily involved in ATP/ADP exchange across the inner mitochondrial membrane (IMM). An increasing number of missense mutations in Ant1 are found to cause dominant diseases that affect skeletal muscle and the central nervous system. These diseases are commonly manifested by fractional mtDNA deletions and mild bioenergetic defects. The mechanism of neuromuscular damage in the diseases is poorly understood. Interestingly, our recent studies in yeast and cultured human cells suggested that the mutant Ant1 is misfolded. This leads to cell death by a novel mechanism that we named mitochondrial Precursor Overaccumulation Stress (mPOS). mPOS is characterized by the toxic accumulation and aggregation of un-imported mitochondrial preproteins in the cytosol. These findings led to the central hypothesis that the mutant Ant1 primarily affects mitochondrial protein import. This results in mPOS in the cytosol, which plays an important role in inducing neural and muscular degeneration. Fractional mtDNA deletions occur independent of nucleotide transport activity, likely as a secondary damage collateral to reduced mitochondrial protein import. In this application, we propose to directly test this hypothesis in mouse models. We successfully generated knock-in (KI) mouse lines expressing misfolded variants of Ant1. Preliminary studies indicated that these mice develop phenotypes consistent with neural and muscular degeneration. In Specific Aim 1, we will use these unique experimental models to test the hypothesis that misfolded Ant1 induces neural and muscular degeneration and mtDNA instability independent of nucleotide transport. In Specific Aim 2, we will use various experimental tools that we developed in yeast, cultured human cells and the Ant1-KI mice to test the hypothesis that the misfolded Ant1 (or Aac2 in yeast) causes structural and functional damage to the mitochondrial protein import machinery and induces mPOS in the cytosol. In Specific Aim 3, we will determine the mechanisms that protect cells against Ant1-induced protein import stress and mPOS. Success of the project will establish a mouse model of protein import stress associated with mPOS. Particularly, validation of the mPOS model would help reconciling the mitochondrial and proteostatic pathways in many neural and muscular degenerative diseases. Finally, the results could have important implications for the understanding and therapy of Ant1-induced diseases, as well as many other clinical conditions that directly or indirectly affect mitochondrial protein import.

Ant1是肌肉/心脏/中枢神经系统（CNS）腺嘌呤核苷酸转位酶的异构体