Tyrosine degradation pathway in mitochondrial dysfunction and aging

摘要 代谢稳态的丧失是衰老的标志，导致对疾病的易感性增加 和增加的脆弱性。尽管已经在不同物种中探索了整体代谢重编程， 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，受影响的代谢途径可以直接针对，铺平了道路，延迟，甚至是一个 逆转模型生物体的衰老，并最终在人类身上。 我们以前证明，酪氨酸降解途径中的酶水平增加， 随着年龄的增长，无论是全身或神经元特异性下调酶的酪氨酸 降解途径显著延长果蝇寿命。从机制上讲，抑制线粒体 电子传递链复合物I（mETC CI）表型模仿衰老并驱动衰老中酶的上调。 酪氨酸降解途径。虽然酪氨酸催化剂的增加对健康有害- 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。也是 目前尚不清楚是否有类似的机制导致酪氨酸衍生的 包括人类在内的哺乳动物的神经递质。 通过我们对潜在的转录因子/调节子的初步筛选，我们鉴定了stonewall， （Stwl）作为一种潜在的转录调节因子（TR），负责应答中达特的上调， 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，并且该过程是保守的， 在哺乳动物中。 在本申请中，我们提出确定Stwl对酪氨酸激酶中的酶水平的影响。 降解途径，酪氨酸衍生的神经递质水平，果蝇的健康和寿命（目标1）; 并测试老化/线粒体功能障碍对酪氨酸降解活性的影响 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 神经传递素

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.