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一个标志，会导致疾病易感性增加并增加虚弱程度。尽管已经在不同物种中探索了全局代谢重编程，人们对驱动这种重编程的机制知之甚少。通过对这些更深入的了解过程中，可以直接针对受影响的代谢途径，为延迟甚至停止铺平道路。逆转模型生物体并最终逆转人类的衰老。我们之前证明酪氨酸降解途径中的酶水平增加随着年龄的增长，酪氨酸酶的全身或神经元特异性下调降解途径显着延长果蝇的寿命。从机制上讲，抑制线粒体电子传递链复合物 I (mETC CI) 可模拟衰老并驱动体内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，驱动这种年龄依赖性上调的机制尚不清楚。这也是尚不清楚是否有类似的机制导致酪氨酸衍生的年龄依赖性减少包括人类在内的哺乳动物的神经递质。通过对潜在转录因子/调节因子的初步筛选，我们确定了石墙 (Stwl) 作为一种前瞻性转录调节因子 (TR)，负责 TAT 的上调反应 mETC CI 抑制。我们的中心假设是抑制 Stwl 可以防止酪氨酸增强与衰老和线粒体功能障碍相关的降解，并且该过程是保守的在哺乳动物中。在此应用中，我们建议确定 Stwl 对酪氨酸中酶水平的影响降解途径、酪氨酸衍生神经递质水平以及果蝇健康和寿命（目标 1）；并测试衰老/线粒体功能障碍是否对酪氨酸降解活性产生影响该途径在哺乳动物中是保守的（目标 2）。我们期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、酪氨酸代谢和生成之间的新联系神经递质。