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Tyrosine degradation pathway in mitochondrial dysfunction and aging

线粒体功能障碍和衰老中的酪氨酸降解途径

基本信息

批准号：
10527038
负责人：
Andrey A Parkhitko
金额：
$ 7.95万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527038
关键词：
Adult Affect Age Aging Animal Model Automobile Driving Biological Models Brain Catabolism Catecholamines Chromatin Citric Acid Cycle Complex Degradation Pathway Disease Dopamine Down-Regulation Drosophila genus Drosophila melanogaster Electron Transport Enzymes Exercise FDA approved Genetic Transcription Health Heterochromatin Homeostasis Human Human Cell Line Knowledge Laboratories Link Liver Longevity Mammals Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Mus Neurons Neurotransmitters Norepinephrine Octopamine Pathway interactions Performance Pharmaceutical Preparations Phenocopy Physiological Plasma Predisposition Process Production Protein Family Proteins Rattus Stress Supplementation Testing Tissues Translating Tyramine Tyrosine Tyrosine Aminotransferase Tyrosine Metabolism Pathway Up-Regulation age effect age related aged base enzyme pathway feeding fly frailty healthspan improved insight interest mitochondrial dysfunction novel overexpression prevent programs prospective response sedentary transcription factor

项目摘要

Abstract Loss of metabolic homeostasis is a hallmark of aging that leads to increased susceptibility to diseases and increased frailty. Although global metabolic reprogramming has been explored in different species, the mechanisms driving this reprogramming are poorly understood. Through a deeper understanding of these processes, the affected metabolic pathways can be directly targeted, paving the way to a delay or even a reversal of aging in model organisms and ultimately in humans. We previously demonstrated that the levels of enzymes in the tyrosine degradation pathway increase with age and that either whole-body or neuronal-specific downregulation of enzymes in the tyrosine degradation pathway significantly extend Drosophila lifespan. Mechanistically, suppression of mitochondrial Electron Transport Chain Complex I (mETC CI) phenocopies aging and drives the upregulation of enzymes in the tyrosine degradation pathway. Although the augmentation of tyrosine catabolism was detrimental to health- and lifespan in our studies, the mechanism driving this age-dependent upregulation is unknown. It is also unknown whether a similar mechanism is responsible for the age-dependent decrease of tyrosine-derived neurotransmitters in mammals including humans. Through our preliminary screen of potential transcription factors/regulators, we identified stonewall (Stwl) as a prospective transcriptional regulator (TR) that is responsible for the upregulation of TAT in response to mETC CI inhibition. Our central hypothesis is that inhibiting Stwl can prevent the augmented tyrosine degradation associated with aging and mitochondrial dysfunction and that this process is conserved in mammals. In this application, we propose to determine the impact of Stwl on the levels of enzymes in the tyrosine degradation pathway, levels of tyrosine-derived neurotransmitters, and Drosophila health- and lifespan (Aim 1); and to test whether the effect of aging/mitochondrial dysfunction on the activity of the tyrosine degradation pathway is conserved in mammals (Aim 2). We expect that the insights we gain will allow us to establish a novel link between aging, mitochondrial dysfunction, tyrosine metabolism, and the production of neurotransmitters.

摘要