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

• 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
• 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

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 代谢动态平衡的丧失是衰老的标志，它会增加疾病的易感性 以及更多的脆弱。尽管已经在不同的物种中探索了全球代谢重新编程，但 人们对这种重新编程的机制知之甚少。通过更深入地了解这些 过程中，受影响的代谢途径可以直接成为靶点，为延迟甚至是 在模式生物中，并最终在人类中逆转衰老。 我们之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，全身或神经元特异性下调酪氨酸酶 降解途径显著延长了果蝇的寿命。从机制上讲，线粒体的抑制 电子传输链复合体I(METC CI)的衰老和驱动酶的上调 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，驱动这种年龄相关性上调的机制尚不清楚。它也是 尚不清楚是否有类似的机制导致酪氨酸衍生物的年龄依赖性下降 包括人类在内的哺乳动物体内的神经递质。 通过我们对潜在转录因子/调节因子的初步筛选，我们确定了石墙 (Stw1)作为一个潜在的转录调节因子(Tr)，负责Tat的上调。 对mETC CI的抑制。我们的中心假设是，抑制Stwl可以防止酪氨酸增加 与衰老和线粒体功能障碍相关的降解，这一过程是保守的 在哺乳动物身上。 在这个应用中，我们建议确定stwl对酪氨酸酶水平的影响。 降解途径、酪氨酸衍生神经递质水平以及果蝇的健康和寿命(目标1)； 并检测衰老/线粒体功能障碍对酪氨酸降解活性的影响 通路在哺乳动物中是保守的(目标2)。我们希望我们所获得的见解将使我们能够建立一个 衰老、线粒体功能障碍、酪氨酸代谢和血管紧张素转换酶生成之间的新联系 神经递质。