Mitochondria, Oxidative Stress and the Kynurenine System, with a Focus on Ageing and Neuroprotection.
Mitochondria, Oxidative Stress and the Kynurenine System, with a Focus on Ageing and Neuroprotection.
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DOI：
10.3390/molecules23010191
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发表时间：
2018-01-17
期刊：
影响因子：
--
通讯作者：
Vécsei L
中科院分区：
文献类型：
--
作者：
Sas K;Szabó E;Vécsei L
在这篇综述中，讨论了衰老的潜在原因。我们试图深入了解线粒体的主要生理功能，并讨论其功能和基因组的改变，这应该是衰老的核心机制。最后，我们提出了潜在的犬尿氨酸途径在衰老过程中的调节作用。线粒体动力学被认为在维持细胞内稳态中具有重要的生理作用。据报道，在衰老过程中，线粒体动力学下降，可能损害线粒体的功能。线粒体生物发生不仅包括线粒体动力学，而且还包括基因转录和翻译的调节，线粒体被认为在衰老过程中的细胞死亡中起着重要作用。mtDNA复制机制的缺陷和mtDNA修复的失败可能导致突变的积累，导致线粒体功能障碍和细胞的生物能量衰竭。活性氧（ROS）在衰老过程中的作用已得到广泛认可。在衰老过程中，可能会发生对mDNA的过度氧化损伤，包括单核苷酸碱基改变、核苷酸碱基对改变、链断裂和交联。已经进化出了一个广泛的DNA缺陷修复库，但它们在衰老过程中不能有效地发挥作用。聚（ADP-核糖）聚合酶（PARP）是一种有助于DNA修复的酶，即，它参与单链DNA切口的修复，启动碱基切除修复（BER）。在广泛的DNA损伤的情况下，PARP-1变得过度活化并迅速耗尽细胞内NAD+和ATP池。这会导致细胞能量严重损失，并导致细胞功能障碍，甚至细胞死亡。犬尿氨酸系统的改变与衰老过程和几种与年龄有关的疾病有关。犬尿氨酸途径将色氨酸（TRP）降解为几种代谢物，尤其是犬尿氨酸（KYN）、犬尿烯酸（KYNA）和喹啉酸（QUIN）。该路线的最终产物是NAD+。第一种代谢反应由TRP-2，3-双加氧酶（TDO）或吲哚胺-2，3-双加氧酶（IDO）介导，后者由炎症诱导，并且被认为在几种疾病和衰老中具有重要作用。研究目前集中在KYN通路上，因为几种中间体具有神经和免疫活性特性，因此能够调节某些脑细胞的活性和炎症反应。在衰老过程中，以及在许多与年龄相关的疾病如肥胖症、血脂异常、高血压、胰岛素抵抗和神经退行性疾病中，已经报道了低度、持续的炎症和IDO的上调。然而，TRP下游catalysts创建一个负反馈回路，通过削弱激活的免疫系统通过几个动作，包括在Th 1反应的下降和Th 2型过程的增强。KYN中间体在大脑兴奋/抑制中的广泛作用及其在调节免疫反应中的作用可能为将来修改一系列年龄相关疾病的病理过程提供了可能性。
In this review, the potential causes of ageing are discussed. We seek to gain insight into the main physiological functions of mitochondria and discuss alterations in their function and the genome, which are supposed to be the central mechanisms in senescence. We conclude by presenting the potential modulating role of the kynurenine pathway in the ageing processes. Mitochondrial dynamics are supposed to have important physiological roles in maintaining cell homeostasis. During ageing, a decrease in mitochondrial dynamics was reported, potentially compromising the function of mitochondria. Mitochondrial biogenesis not only encompasses mitochondrial dynamics, but also the regulation of transcription and translation of genes, and mitochondria are supposed to play a prominent role in cell death during senescence. Defects in the mtDNA replication machinery and failure in the repair of mtDNA might result in the accumulation of mutations, leading to mitochondrial dysfunction and bioenergetic failure of the cell. The role of reactive oxygen species (ROS) in the ageing processes is widely acknowledged. Exaggerated oxidative damage to mDNA is supposed to take place during senescence, including single-nucleotide base alterations, nucleotide base pair alterations, chain breaks and cross linkage. A broad repertoire for the repair of DNA faults has evolved, but they do not function efficiently during senescence. Poly (ADP-ribose) polymerase (PARP) is an enzyme that assists in DNA repair, i.e., it participates in the repair of single-stranded DNA nicks, initiating base excision repair (BER). In the case of extensive DNA damage, PARP-1 becomes overactivated and rapidly depletes the intracellular NAD+ and ATP pools. This results in a profound energy loss of the cell and leads to cell dysfunction, or even cell death. Alterations in the kynurenine system have been linked with ageing processes and several age-related disorders. The kynurenine pathway degrades tryptophan (TRP) to several metabolites, among others kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN). The end product of the route is NAD+. The first metabolic reaction is mediated by TRP-2,3-dioxygenase (TDO) or indolamine-2,3-dioxygenases (IDO), the latter being induced by inflammation, and it is thought to have a significant role in several disorders and in ageing. Research is currently focusing on the KYN pathway, since several intermediates possess neuro- and immunoactive properties, and hence are capable of modulating the activity of certain brain cells and inflammatory responses. During ageing, and in many age-associated disorders like obesity, dyslipidaemia, hypertension, insulin resistance and neurodegenerative diseases, low-grade, sustained inflammation and upregulation of IDO have been reported. However, TRP downstream catabolites create a negative feedback loop by weakening the activated immune system through several actions, including a decline in the Th1 response and an enhancement of Th2-type processes. The broad actions of the KYN-intermediates in brain excitation/inhibition and their role in regulating immune responses may provide the possibility of modifying the pathological processes in an array of age-associated diseases in the future.
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影响因子：
4.7
作者：
de Bie, Josien;Guest, Jade;Grant, Ross
通讯作者：
Grant, Ross
影响因子：
11.4
作者：
Areti A;Yerra VG;Naidu V;Kumar A
通讯作者：
Kumar A
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
--
作者：
Chistiakov DA;Sobenin IA;Revin VV;Orekhov AN;Bobryshev YV
通讯作者：
Bobryshev YV
DOI：
10.1186/s13058-014-0410-1
发表时间：
2014-07-25
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Chen JY;Li CF;Kuo CC;Tsai KK;Hou MF;Hung WC
通讯作者：
Hung WC