Advances in Clinical Medicine
Vol. 09  No. 01 ( 2019 ), Article ID: 28526 , 6 pages
10.12677/ACM.2019.91006

Progress of Melatonin in Reducing Mitochondrial Injury by Interacting with Sirt3

Yanan Hu, Fei Han*

Department of Anesthesiology, The Affiliated Oncology Hospital, Harbin Medical University, Harbin Heilongjiang

Received: Dec. 24th, 2018; accepted: Jan. 11th, 2019; published: Jan. 18th, 2019

ABSTRACT

Background: Melatonin is a special indole amine derived from the pineal gland, with multiple properties of antioxidant, anti-aging and metabolic. Recent years, studies related to the role of melatonin in cells have gradually focused on mitochondria. In mitochondria, melatonin stimulates Sirt3 activity. It regulates the activity of Foxo3a, SOD2 and the most metabolic enzymes in TCA cycles by strengthening the deacetylation effect of Sirt3, and thus plays a protective role in diseases such as cardiovascular disease, liver and kidney injury, and heavy metal hazards. Objective: To review the related literatures on the interaction between melatonin and Sirt3 in reducing mitochondria injury. Content: Based on series studies, this article illuminated the expression, metastasis and co-localization of melatonin and Sirt3 in mitochondria, and summarized the protective mechanism of melatonin in multiple organs. Trend: The interaction between Melatonin and Sirt3 will be one of the most valuable research field in mitochondria protection with both shared multiple signal pathways.

Keywords:Melatonin, Sirtuin 3, Protection of Mitochondria

Sirt3在褪黑素减少线粒体损伤的研究进展

胡亚楠,韩非*

哈尔滨医科大学附属肿瘤医院麻醉科,黑龙江 哈尔滨

收稿日期:2018年12月24日;录用日期:2019年1月11日;发布日期:2019年1月18日

摘 要

背景:褪黑激素是一种起源于松果腺的特殊吲哚胺,具有抗氧化,抗衰老和调控代谢的特性,近年来,与褪黑激素在细胞中作用的相关研究逐渐集中于线粒体。在线粒体中,褪黑激素可以刺激沉默信息调控蛋白3 (Sirt3)活性,通过加强其去乙酰化作用调控Foxo3a、SOD2及TCA周期中大部分代谢酶的活性,进而在心血管疾病、肝肾损伤、重金属危害等疾病中发挥保护作用。目的:对褪黑激素与Sirt3相互作用减少线粒体损伤的相关文献进行综述。内容:整理和阐述了褪黑激素与Sirt3在线粒体的表达、转移、共定位,及对不同器官的保护作用机制。趋向:褪黑激素与Sirt3在线粒体内共享多种信号通路,两者的相互作用可能是未来一个富有成效的研究领域。

关键词 :褪黑激素,Sirt3,线粒体功能保护

Copyright © 2019 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

褪黑激素(N-乙酰基-5-甲氧基色胺)是一种起源于松果腺的特殊吲哚胺,研究报道其具有显著抗氧化,抗衰老和调控代谢的特性,对多种心血管疾病,包括心肌缺血再灌注,高血压和心力衰竭等都表现出有益的作用 [1] [2]。最近,关于褪黑激素的保护性信号通路受到越来越多的关注,其重要的机制之一是通过介导激活线粒体沉默信息调节因子3 (Sirt3)在疾病发生中发挥作用。目前,研究发现褪黑激素与Sirt3在线粒体共定位,通过增强其活性及去乙酰化作用调控多种功能蛋白如叉头框3a (Foxo3a),超氧化物歧化酶(SOD2)和雷帕霉素受体(mTOR)等的活性,进而减少动脉硬化等心血管疾病发生、肝肾辐射伤及生殖器官衰老。本文就褪黑素与Sirt3相互作用的相关研究进行总结。

2. 褪黑素在线粒体的合成和转移

褪黑激素是一种具有多种作用的吲哚胺,在大量食用植物产品和药用植物,如葡萄酒,橄榄油,番茄,啤酒等被鉴定出来。在哺乳动物中最初被认为仅在松果体合成,但很快发现它也在视网膜中产生,以光周期依赖性生理方式产生和释放到脑脊液和血液中,并通过视交叉上核,外周振荡器,和全组织范围内的生物钟进行调节 [3]。然而细胞内褪黑激素水平显然不是来自血液,因为当测量松果腺切除的动物的细胞内褪黑激素浓度时,虽然循环水平基本降低到零,但在脑核或线粒体中并没有受到影响。随后,在许多富含线粒体的细胞如胃肠道、免疫系统细胞、脾脏、肝脏、肾脏和心脏中都发现了褪黑素的产生。为了解释这种不断扩大的细胞阵列,许多生物实验探索了褪黑激素在线粒体中转移和合成的机制。Hevia等人 [4] 首次尝试确定褪黑激素通过膜的主动运输方式进入细胞,随后将所涉及的蛋白质鉴定为GLUT1转运蛋白。Huo及其同事 [5] 通过分析研究寡肽转运蛋白的动力学作用,定义了褪黑激素可以进入细胞和线粒体的另一种方法,即通过寡肽转运蛋白PEPT1/2参与细胞和线粒体膜转移过程,促进褪黑素在细胞内,特别是线粒体内的摄取和保留。Suofu及其同事 [6] 通过一项完整的实验确定了细胞中褪黑激素形成的位置。他们在非突触体脑的线粒体中检测到产生褪黑激素的两种末端酶AANAT和HIOMT以及AANAT伴侣14-3-3ζ位于线粒体中。根据He等人 [7] 关于卵母细胞线粒体产生褪黑激素且分布到全生物体范围内线粒体的研究结果,证实了所有细胞的线粒体都可以根据需要制造褪黑激素,如氧化应激,缺血再灌注等条件下,褪黑激素的产生是诱导型的,且具组织特异性。

3. 褪黑素与Sirt3在线粒体的共定位

哺乳动物细胞中的Sirtuin家族是第III类组蛋白去乙酰化酶,包括七名成员(Sirt1-7),每个Sirtuin都有一个保守的NAD+结合域,统称为细胞酰基。Sirtuin蛋白具有多种酶活性和功能,它们在亚细胞水平差异分布,其中最著名的是位于细胞核的Sirt1和位于线粒体的Sirt3 [8] [9]。通过介导赖氨酸残基的翻译后修饰,Sirt3调节线粒体呼吸及氧化还原状态,减少氧化应激损伤等多种分子途径。由于褪黑激素与Sirt3太多相似的作用通路,人们推测两者之间是相互关联。研究表明与Sirt3一起存在于线粒体中的褪黑素会影响这种Sirtuin蛋白的脱乙酰化作用,且线粒体Sirt3容易受到外源提供的褪黑激素调节 [10]。

4. 褪黑素与Sirt3的相互作用

实验证据表明褪黑激素可以增强Sirt3的活性及去乙酰化酶作用,介导多种蛋白信号通路减少氧化应激,细胞凋亡,线粒体自噬等。表1列举了代表性的参考文献,记录了褪黑激素在缺血/再灌注损伤、重金属毒性的损害中对多种器官的保护功能。

Table 1. Protective effect of melatonin on multiple organs

表1. 褪黑素的多器官保护功能

4.1. 心血管保护

褪黑激素在多种器官中均被报道可以保护心血管功能。在大鼠冠状动脉结扎模型中,Yu及其同事检测了褪黑激素在线粒体水平的作用 [20]。研究证实褪黑激素通过增加ATP产生,改善呼吸链功能(复合物II,III和IV),激活超氧化物歧化酶(SOD2),限制心肌细胞凋亡和减少H2O2生成来改善心脏缺血再灌注损伤。同时,褪黑激素的有益作用源于其激活腺苷磷酸激活激酶(AMPK)-过氧化物酶体增殖物受体γ辅激活因子1α (PGC-1α)-Sirt3信号传导,并升高核因子(NRF)和线粒体转录因子A(TFAM)的表达。此外,超声心动图监测显示褪黑激素减轻了糖尿病小鼠的左心室重塑并保持了心脏功能,其机制被证实通过抑制Mst磷酸化,导致Sirt3活性和抗氧化作用增强 [21]。冠状动脉内皮细胞功能障碍是动脉粥样硬化病变发展所必需的特征,褪黑激素被证明可以维持细胞膜的最佳流动性,从而保护它们免受自由基损害,降低脂质过氧化,最终抑制斑块形成和其他后续的负面影响 [22]。此外,在脂多糖处理后的人脐静脉内皮细胞的体外模型中,褪黑激素降低了氧化应激水平(NOX-1/NOX-2),减少了炎症反应(TNF-α/NF-kB)、细胞死亡(caspase 3/PARP)和线粒体功能障碍(cyt-C)。然而当线粒体Sirt3沉默(用siRNA)时,褪黑激素的体外作用不再存在,这一发现进一步表明褪黑激素在线粒体中的抗氧化作用很大程度上依赖于Sirt3脱乙酰化 [23]。

4.2. 肝功能保护

褪黑激素已成功用于对抗实验动物慢性摄入氟化物引起的肝损伤 [24]。在分子水平上,褪黑激素刺激Sirt3脱乙酰化,导致超氧化物的快速歧化,同时触发了Foxo3a的DNA结合,进而减少线粒体氧化应激 [25]。值得注意的是,褪黑激素通过激活PGC-1α进而提高Sirt3的表达。对细胞信号传导途径谱分析系统和特异性途径抑制的分析表明,褪黑激素通激活PI3K/AKT信号传导途径增强PGC-1α表达,并通过ERR结合元件(ERRE)映射到Sirt3启动子区域。重要的是,通过使用膜褪黑素受体阻滞剂,抑制MT1阻断了褪黑激素激活的PI3K/AKT-PGC-1α-Sirt3信号传导,从而证明褪黑激素的这一作用是由MT1受体介导的。

4.3. 生殖器官保护

啮齿动物(如人类)肥胖导致Sirt3的乙酰化,这降低了其活性并且由于无限制的ROS产生而导致灾难性细胞损伤。正如预期的那样,Han等人将褪黑激素喂给肥胖大鼠,极大地改善了卵母细胞的质量和受精率,这伴随着Sirt3的活化(脱乙酰化),其诱导SOD2最终减少卵母细胞中的氧化应激 [19]。当褪黑激素长期口服给予衰老的雌性小鼠和大鼠时,相比于未用褪黑激素治疗的年龄匹配的对照组,其生殖功能和表现明显改善 [26]。在小鼠中,褪黑激素治疗伴随着卵巢颗粒细胞中增强的Sirt3活性以及Foxo3a向细胞核的易位,其中它与SOD2和过氧化氢酶(CAT)的启动子结合 [27]。除了Sirtuins的上调,褪黑激素可能由于其直接的自由基清除活动,端粒酶的刺激,减少自噬等而推迟卵巢衰老。如图1,总结了关于褪黑激素和线粒体Sirt3相互作用的机制通路 [28]。

Figure 1. Melatonin regulates mitochondrial function through Sirt3

图1. 褪黑素通过Sirt3调控线粒体功能

5. 结语

近年来,与褪黑激素在细胞中的作用相关的研究逐渐集中于线粒体。由于褪黑激素是一种强大的氧化应激抑制剂,它在线粒体水平上的作用可能不是偶然的,而且考虑到它的高度保护作用是必要的。Sirt3在线粒体中具有多种功能,它影响呼吸链复合物并提高ATP产生,影响柠檬酸循环中的酶,控制氨基酸代谢和脂肪酸氧化。结合Sirt3在线粒体的动力学影响,褪黑激素与其共享表观遗传行为的结果,包括对线粒体自噬、线粒体生物能量学、融合或裂变的影响,未来以Sirt3为靶点,从药效学角度进一步探索褪黑素在抑制癌症转移,减少辐射损伤,及预防缺血再灌注线粒体应激等领域在未来将富有显著成效。此外,褪黑素在其他亚细胞区室中的功能也是值得探索的领域。

致谢

由衷地感谢哈尔滨医科大学附属肿瘤医院对该文章的资金支持与帮助。

基金项目

国家自然科学基金面上项目(81871515);Nn10培育基金项目(Nn10py2017-05)。

文章引用

胡亚楠,韩 非. Sirt3在褪黑素减少线粒体损伤的研究进展
Progress of Melatonin in Reducing Mitochondrial Injury by Interacting with Sirt3[J]. 临床医学进展, 2019, 09(01): 27-32. https://doi.org/10.12677/ACM.2019.91006

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NOTES

*通讯作者。

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