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Mitochondrial metabolism and the Lon-PDH axis

线粒体代谢和 Lon-PDH 轴

基本信息

批准号：
10379257
负责人：
CAROLYN K SUZUKI
金额：
$ 32.17万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
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：
2020-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379257
关键词：
Acetyl Coenzyme A Acetylation Animal Model Architecture Astrocytes Atrophic Brain Carbohydrates Catabolism Cells Cellular Stress Cerebrum Citric Acid Cycle Complex Data Defect Dietary Intervention Disease Energy Metabolism Energy-Generating Resources Enzymes Erythrocytes Failure Fatty Acids Fibroblasts Functional disorder Gatekeeping Generations Genes Glucose Glutamine Glycolysis Glycolysis Inhibition Goals Heart Diseases Human Impairment Investigation Ketone Bodies Knowledge Leucine Link Malignant Neoplasms Measures Mediating Medium chain fatty acid Metabolic Metabolism Missense Mutation Mitochondria Modification Molecular Molecular Machines Mutation Nerve Degeneration Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Neurons Outcome Oxidative Phosphorylation Oxides PDH kinase Parents Pathogenicity Pathway interactions Patients Pharmacology Phosphorylation Positioning Attribute Post-Translational Protein Processing Production Proline Proteins Proteolysis Proteomics Pyruvate Pyruvate Dehydrogenase (Lipoamide)-Phosphatase Pyruvate Dehydrogenase Complex Pyruvate Dehydrogenase E1 Reaction Regulation Siblings Skin Stream Testing Transcript Variant Work amino acid metabolism brain cell dihydrolipoamide dehydrogenase dihydrolipoyllysine-residue acetyltransferase endopeptidase La experimental study fatty acid oxidation high throughput screening induced pluripotent stem cell intermolecular interaction metabolomics mitochondrial metabolism mutant novel oxidation proteostasis pyruvate dehydrogenase response stem cell differentiation therapeutic protein uptake

项目摘要

The human Lon protease is a master regulator of mitochondrial proteostasis, which is essential for regulating mitochondrial energy metabolism and mitigating cell stress. We recently identified a novel pathogenic variant in the LONP1 gene encoding Lon, in two siblings with profound neurologic impairment, cerebral and cerebellar atrophy, in which proline at position 761 was replaced by leucine (Lon-P761L). Primary skin fibroblasts from these siblings, showed that the activity of pyruvate dehydrogenase (PDH) was substantially reduced. PDH deficiency was caused by the failure of Lon-P761L to degrade the phosphorylated E1a subunit of PDH, which accumulates and inhibits PDH activity. PDH is the central gatekeeper linking glycolysis to the tricarboxylic acid (TCA) cycle, and is also a key regulatory node for glucose and fatty acid catabolism. Our long term goal is to elucidate why homozygous Lon-P761L expression causes severe neurologic dysfunction and neurodegeneration. Glucose is the brain’s principal source of energy. Neurons generate ATP almost exclusively by glucose oxidization, thus fully functional PDH activity is crucial. Astrocytes by contrast, have broader metabolic capacity and supply neurons with lactate, glutamine and ketone bodies, which are used to form acetyl CoA and TCA cycle intermediates required for glucose oxidation. We hypothesize that wild type Lon regulates the architecture and activities of the PDH complex, and modulates upstream and downstream effectors, to calibrate mitochondrial metabolism and energetics. In this project, we will employ patient-and parent-derived fibroblasts, and also fibroblasts that have been reprogrammed to generate induced pluripotent stem cells (iPSCs). These iPSCs will be differentiated into neurons and astrocytes. Using the patient- and parent- derived fibroblasts, Aim 1 will test the hypothesis that Lon-mediated degradation regulates the architecture and activity of the PDH complex. Aim 2 will identify the up- and down-stream modulators of the Lon-PDH axis, which are altered in cells expressing wild type Lon versus Lon-P761L. In Aim 3, we will investigate the regulation of PDH by Lon in iPSCs differentiated into neurons and astrocytes. Our investigation will establish new molecular mechanisms for the Lon-dependent regulation of PDH. The knowledge gained will also help to identify potential therapeutic protein targets (e.g. PDK, PDP, Lon), pharmacologic and dietary interventions for increasing PDH activity and/or for treating PDH deficiency associated with Lon dysfunction. These outcomes have a broader impact for understanding how PDH activity and mitochondrial metabolism can be calibrated in both rare and more common disorders such as heart disease, cancer and neurodegeneration.

人类Lon蛋白酶是线粒体蛋白质平衡的主要调节因子，这对人体的健康至关重要