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：
10707251
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/10707251
关键词：
Adult Affect Age Aging 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 Methylation Mitochondria Modeling Molecular Mus Neurons Neurotransmitters Norepinephrine Octopamine Pathway interactions Performance Pharmaceutical Preparations Phenocopy Physiological Plasma Predisposition Process Production Protein Family Proteins Rattus Route Stress Supplementation Testing Tissues Translating Tyramine Tyrosine Tyrosine Aminotransferase Tyrosine Metabolism Pathway Up-Regulation age effect age related aged enzyme pathway feeding fly frailty healthspan improved insight interest mitochondrial dysfunction model organism 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.

抽象的代谢稳态的丧失是衰老的标志，导致对疾病的敏感性增加并增加了脆弱。尽管在不同物种中探索了全球代谢重编程，但推动重编程的机制知之甚少。通过对这些的深入了解过程，受影响的代谢途径可以直接瞄准，铺平了延迟甚至模型生物的衰老逆转，最终在人类中。我们先前证明了酪氨酸降解途径中的酶水平增加随着年龄的增长和酪氨酸中酶的全身或神经元特异性下调降解途径显着延长了果蝇的寿命。机械上，线粒体的抑制电子传输链复合物I（METC CI）表型衰老，并驱动酶的上调酪氨酸降解途径。尽管酪氨酸分解代谢的增强对健康有害 - 在我们的研究中，驱动这种依赖年龄上调的机制尚不清楚。也是尚不清楚类似的机制是否导致酪氨酸衍生的年龄依赖性降低包括人类在内的哺乳动物中的神经递质。通过我们对潜在转录因子/调节器的初步屏幕，我们确定了石墙（STWL）作为一种前瞻性转录调节器（TR），负责TAT的上调进行METC CI抑制。我们的中心假设是抑制STWL可以防止增强的酪氨酸与衰老和线粒体功能障碍相关的降解，此过程是保守的在哺乳动物中。在此应用中，我们建议确定STWL对酪氨酸酶水平的影响降解途径，酪氨酸衍生的神经递质的水平以及果蝇健康和寿命（AIM 1）；并测试衰老/线粒体功能障碍对酪氨酸降解活性的影响途径在哺乳动物中是保守的（AIM 2）。我们希望我们获得的见解将使我们能够建立一个衰老，线粒体功能障碍，酪氨酸代谢和产生之间的新联系神经递质。