PINK1/Parkin介导的线粒体自噬及其在肝脏疾病发生发展中的作用机制

线粒体自噬是指细胞通过自噬的机制选择性地清除受损线粒体的过程。线粒体自噬的调控机制有几种,但PINK1/Parkin途径被认为是线粒体自噬的主要途径,这一自噬机制在帕金森等多种疾病的发病中有重要作用。介绍了PINK1/Parkin介导的线粒体自噬机制及其在肝脏相关疾病(如非酒精性脂肪性肝病、肝纤维化、肝细胞癌等)中的作用,以期为疾病的治疗提供新的线索和思路。     

线粒体自噬在心血管疾病中的作用

自噬对于组成心血管系统的细胞（如心肌细胞、内皮细胞和血管平滑肌细胞等）的细胞内稳态和生理功能的维持具有重要作用。线粒体自噬是以损伤的线粒体作为自噬底物的一种选择性自噬。由于线粒体是生物能量的主要来源且心血管系统对能量要求较高，线粒体自噬在心血管稳态的维持中尤为重要。研究证实线粒体自噬在心肌梗死、心力衰竭和动脉粥样硬化等疾病中扮演重要角色。本文概述了线粒体自噬的主要调控通路，并阐述了线粒体自噬与心血管疾病之间的密切联系。     

中药成分干预线粒体自噬对慢性心力衰竭影响的研究进展及强心颗粒的潜在作用机制探讨

综述线粒体自噬对慢性心力衰竭(CHF)的致病机制以及中药成分调控线粒体自噬方面的研究进展,并运用网络药理学分析名中医卢健棋教授临床诊治CHF的经验方强心颗粒中君药对CHF影响的潜在作用机制。表明线粒体自噬与CHF的发生与转归关系密切,同时中药成分可通过多靶点、多途径调控线粒体自噬水平来防治CHF。     

细胞自噬在糖尿病性心肌病中的研究进展

细胞自噬是受多基因调控的动态过程。自噬可通过控制蛋白质质量,维持心肌细胞的能量平衡与存活,心肌细胞自噬水平异常降低或升高都会导致心肌损伤。不同情况下自噬在糖尿病性心肌病损伤中作用不同。1型糖尿病动物模型中心肌自噬水平降低,对心肌细胞起保护作用;2型糖尿病动物模型中自噬被激活。该文就自噬在糖尿病心肌病中的研究进展作简要介绍。     

老年人心肌细胞自噬的变化及其调控机制研究进展

心肌细胞自噬对维持正常心脏结构和功能起重要作用。近年来的研究结果表明老年人心肌细胞自噬功能降低,老年人心肌自噬基因Atg5、Atg7和Beclin1表达降低;心肌细胞自噬下调与磷脂酰肌醇3-激酶/丝氨酸-苏氨酸激酶/雷帕霉素靶蛋白和单磷酸腺苷激活的蛋白激酶及SIRT1信号通路失调有关;此外,活性氧及一些神经内分泌因子也可介导老年人心肌细胞自噬下调。调控心肌细胞自噬将为老年人心肌病的预防和治疗提供新的途径。     

哺乳动物雷帕霉素靶蛋白介导的自噬在心血管疾病中作用的研究进展

自噬是生物进化过程中高度保守、依赖溶酶体的胞内降解途径。在心血管系统中,基础水平的自噬是维持心脏结构和功能稳态的一种机制;在应激状态下,自噬适度激活可保护心肌细胞免受应激损伤,而过度激活则会加重心肌损伤,从而参与多种心血管疾病的病理生理过程。生物体内存在多种自噬调控机制,其中哺乳动物雷帕霉素靶蛋白是自噬的关键负调控因子,研究其介导的自噬在心血管疾病中的作用机制,有助于探索临床预防和治疗心血管疾病的新靶点。     

线粒体动力学、线粒体自噬和心血管疾病

线粒体是一种动态的细胞器,通过响应各种代谢和环境的信号, 分裂和融合改变其形态和结构,从而维持细胞的正常功能。它们短暂而快速的形态变化对于细胞周期、免疫、凋亡和线粒体自噬的质量控制等许多复杂的细胞过程至关重要。线粒体自噬与线粒体质量控制密切相关,通过将受损的功能障碍的线粒体转运到溶酶体进行降解,促进心肌细胞受损线粒体的更新,并有效地抑制功能障碍线粒体的积累。由于心脏作为一个复杂而高耗能的器官,心肌细胞严重地依赖线粒体氧化代谢过程作为其能量和营养供应的来源。许多研究表明,线粒体融合、分裂和线粒体自噬的诸多影响和调控功能的因子都与各种心血管疾病有关,维持线粒体的功能和其完整性对正常心肌细胞的运行是至关重要的。在这篇的综述中,我们将重点概述一下线粒体的融合、分裂和线粒体自噬的诸多调控因子与心血管疾病的最新研究进展。     

Parkin介导的线粒体自噬在高糖高脂导致的心肌细胞损伤中的保护作用

目的 明确Parkin（一种E3泛素化连接酶）介导的线粒体自噬对高糖高脂导致的原代心肌细胞损伤的保护作用。 方法 以LV-lacZ（LacZ空病毒）或LV-Parkin（Parkin过表达慢病毒）转染SD大鼠原代心肌细胞48 h,再用含葡萄糖（5.5 mmol/L NG）的培养基或含棕榈酸盐（500 μmol/L HF）和葡萄糖（25 mmol/L HG）的高糖高脂培养基培养心肌细胞24 h。 实验分组:①阴性对照组（NG-LacZ）,②正常Parkin过表达组（NG-Parkin）,③高糖高脂阴性对照组（HG-HF-LacZ）,④高糖高脂Parkin过表达组（HG-HF-Parkin）。用Western blot法检测PTEN介导的假定激酶蛋白1（PINK1）、Parkin、P62（一种自噬相关蛋白）、微管相关蛋白1轻链3（LC3）蛋白表达水平。采用JC-1染色法检测活细胞内线粒体膜电位水平。免疫荧光法检测自噬体数量,TUNEL法检测细胞凋亡率。 结果 与对照组相比,高糖高脂处理的原代心肌细胞自噬相关蛋白LC3-Ⅱ,P62表达水平上调（P<0.05）,PINK1表达未发生统计学差异,Parkin表达水平下调（P<0.05）,自噬体数量增多,线粒体膜电位下降功能损伤,心肌细胞凋亡率升高（P<0.05）。而用高糖高脂处理LV-Parkin转染的心肌细胞,LC3-Ⅱ蛋白表达水平进一步升高（P<0.05）,而P62表达水平显著下降（P<0.05）,自噬体数量进一步增多,细胞内线粒体膜电位水平上升,心肌细胞凋亡率下降（P<0.05）。 结论 高糖高脂可引起SD大鼠原代心肌细胞自噬流量降低,自噬小体增多,线粒体自噬发生障碍。Parkin过表达慢病毒通过激活心肌细胞内线粒体自噬途径,提高自噬流量,改善线粒体功能,降低心肌细胞凋亡率。     

选择性自噬和动脉粥样硬化

选择性自噬对降解的底物蛋白具有专一性,包括线粒体自噬、脂噬、炎症小体自噬、内质网自噬、过氧化物酶体自噬、聚集体自噬、核糖体自噬等。动脉粥样硬化(As)是一种慢性炎症性病变,其主要特征包括脂质堆积、泡沫细胞形成、内皮细胞功能障碍、血管平滑肌细胞异常增殖和局部炎症。近年来,大量研究提示选择性自噬参与As的发生发展。文章综述了选择性自噬的调控机制,以及线粒体自噬、脂噬、炎症小体自噬、内质网自噬和过氧化物酶体自噬在As中的作用及其分子机制,以期为As的防治提供新思路。     

线粒体动力学和线粒体自噬与心血管疾病的研究进展

线粒体是一种动态的细胞器,通过响应各种代谢和环境的信号,分裂和融合改变其形态和结构,从而维持细胞的正常功能。它们短暂而快速的形态变化对于细胞周期、免疫、凋亡和线粒体质量控制等许多复杂的细胞过程至关重要。线粒体自噬与线粒体质量控制密切相关,通过将受损的功能障碍的线粒体转运到溶酶体进行降解,促进心肌细胞受损线粒体的更新,并有效地抑制功能障碍线粒体的积累。由于心脏作为一个复杂而高耗能的器官,心肌细胞严重地依赖线粒体氧化代谢过程作为其能量和营养供应的来源。许多研究表明,线粒体融合、分裂和线粒体自噬的诸多影响和调控功能的因子都与各种心血管疾病有关,维持线粒体的功能和其完整性对正常心肌细胞的运行是至关重要的。本综述将重点概述线粒体的融合、分裂和线粒体自噬的诸多调控因子与心血管疾病的最新研究进展。     

中药保护心肌缺血损伤的非循环机制研究进展

中药保护心肌缺血损伤的非循环机制主要包括抑制心肌细胞凋亡、心肌缺血预处理、改善心肌超微结构、心肌酶和免疫功能调节.中药可通过非循环机制增强心肌细胞内源性抗损伤能力,内源性调控保护可能是更有效的心肌保护策略,体现了中西医结合治疗心血管疾病能从整体出发多层面、多靶点发挥作用的优势.     

去乙酰化酶Sirtuins和细胞衰老与动脉粥样硬化的研究进展

细胞衰老是由自身老化或外部刺激诱发的细胞周期停滞。动脉粥样硬化是冠心病的基本病理生理学特征。最新研究发现,细胞衰老是动脉粥样硬化发生发展的重要机制之一。Sirtuins是一类能够调节细胞新陈代谢并参与多种细胞生理功能的去乙酰化酶。以往研究已经揭示了Sirtuins的抗衰老作用,认为Sirtuins是一种与长寿相关的蛋白,可通过调节细胞衰老使动脉粥样硬化得到抑制或逆转。基于此,本文回顾了Sirtuins和细胞衰老与动脉粥样硬化的最新研究发现,并探讨Sirtuins活化作为动脉粥样硬化治疗新靶点的可行性。     

自噬在天然药物活性成分抗心血管衰老中的作用

心血管系统维持着机体正常的生命活动,心血管系统衰老可引发高血压、动脉粥样硬化、心力衰竭、心肌梗死等疾病。自噬是一种溶酶体依赖性降解途径,其水平随着年龄增加而逐渐降低,一方面提高机体自噬可延缓细胞和组织衰老,另一方面自噬水平的过度激活可诱导细胞自噬性死亡、加速衰老。某些天然药物活性成分能调节自噬,并改善心血管系统衰老。它们可能是通过调节细胞自噬发挥对心血管系统衰老的保护作用。因此,文章就自噬在天然药物活性成分延缓心血管系统衰老中的作用及研究进展进行综述。     

Impaired quality control of mitochondria: Aging from a new perspective

Mitochondria fulfill a number of essential cellular functions and play a key role in the aging process. Reactive oxygen species (ROS) are predominantly generated in this organelle but next to inducing oxidative damage they act as signaling molecules. Autophagy is regulated by signaling ROS and is known to affect aging as well as neurodegenerative diseases. Many cellular components that influence autophagy are linked to longevity such as members of the sirtuin protein family. Recent studies further link mitochondrial dynamics to the removal of dysfunctional mitochondria by mitophagy, thereby representing a novel mechanism for the quality control of mitochondria. Here we summarize the current views on how mitochondrial function is linked to aging and we propose that quality control of mitochondria has a crucial role in counteracting the aging process.     

Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways

Platelet activation is a major (patho‐) physiological mechanism that underlies ischemia/reperfusion (I/R) injury. In this study, we explored the molecular signals for platelet hyperactivity and investigated the beneficial effects of melatonin on platelet reactivity in response to I/R injury. After reperfusion, peroxisome proliferator‐activated receptor γ (PPARγ) was progressively downregulated in patients with acute myocardial infarction undergoing coronary artery bypass grafting (CABG) surgery and in mice with I/R injury model. Loss of PPARγ was closely associated with FUN14 domain containing 1 (FUNDC1) dephosphorylation and mitophagy activation, leading to increased mitochondrial electron transport chain complex (ETC.) activity, enhanced mitochondrial respiratory function, and elevated ATP production. The improved mitochondrial function strongly contributed to platelet aggregation, spreading, expression of P‐selectin, and final formation of micro‐thromboses, eventually resulting in myocardial dysfunction and microvascular structural destruction. However, melatonin powerfully suppressed platelet activation via restoration of the PPARγ content in platelets, which subsequently blocked FUNDC1‐required mitophagy, mitochondrial energy production, platelet hyperactivity, and cardiac I/R injury. In contrast, genetic ablation of PPARγ in platelet abolished the beneficial effects of melatonin on mitophagy, mitochondrial ATP supply, and platelet activation. Our results lay the foundation for the molecular mechanism of platelet activation in response to I/R injury and highlight that the manipulation of the PPARγ/FUNDC1/mitophagy pathway by melatonin could be a novel strategy for cardioprotection in the setting of cardiac I/R injury.     

Melatonin attenuates myocardial ischemia‐reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK‐OPA1 signaling pathways

Optic atrophy 1 (OPA1)‐related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1‐related mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia‐reperfusion (I/R) injury. Our results indicated that OPA1, mitochondrial fusion, and mitophagy were significantly repressed by I/R injury, accompanied by infarction area expansion, heart dysfunction, myocardial inflammation, and cardiomyocyte oxidative stress. However, melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on OPA1‐related mitochondrial fusion/mitophagy. At the molecular level, OPA1‐related mitochondrial fusion/mitophagy, which was normalized by melatonin, substantially rectified the excessive mitochondrial fission, promoted mitochondria energy metabolism, sustained mitochondrial function, and blocked cardiomyocyte caspase‐9‐involved mitochondrial apoptosis. However, genetic approaches with a cardiac‐specific knockout of OPA1 abolished the beneficial effects of melatonin on cardiomyocyte survival and mitochondrial homeostasis in vivo and in vitro. Furthermore, we demonstrated that melatonin affected OPA1 stabilization via the AMPK signaling pathway and that blockade of AMPK repressed OPA1 expression and compromised the cardioprotective action of melatonin. Overall, our results confirm that OPA1‐related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac I/R injury. Moreover, manipulation of the AMPK‐OPA1‐mitochondrial fusion/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury.     

Parkin in cancer: Mitophagy-related/unrelated tasks

Dysfunctional mitochondria may produce excessive reactive oxygen species, thus inducing DNA damage, which may be oncogenic if not repaired. As a major role of the PINK1-Parkin pathway involves selective autophagic clearance of damaged mitochondria via a process termed mitophagy, Parkin-mediated mitophagy may be a tumorsuppressive mechanism. As an alternative mechanism for tumor inhibition beyond mitophagy, Parkin has been reported to have other oncosuppressive functions such as DNA repair, negative regulation of cell proliferation and stimulation of p53 tumor suppressor function. The authors recently reported that acute ethanol-induced mitophagy in hepatocytes was associated with Parkin mitochondrial translocation and colocalization with accumulated 8-OHd G(a marker of DNA damage and mutagenicity). This finding suggests:(1) the possibility of Parkin-mediated repair of damaged mitochondrial DNA in hepatocytes of ethanol-treated rats(ETRs) as an oncosuppressive mechanism; and(2) potential induction of cytoprotective mitophagy in ETR hepatocytes if mitochondrial damage is too severe to be repaired. Below is a summary of the various roles Parkin plays in tumor suppression, which may or may not be related to mitophagy. A proper understanding of the various tasks performed by Parkin in tumorigenesis may help in cancer therapy by allowing the PINK1-Parkin pathway to be targeted.     

Melatonin attenuates traumatic brain injury‐induced inflammation: a possible role for mitophagy

Melatonin functions as a crucial mediator of sterile neuroinflammation; however, the underlying mechanisms remain poorly understood. Dysfunctional mitochondria, a main source of reactive oxygen species, are impacted in inflammation activation. This study aimed to examine the effect of melatonin on inflammation via elimination of damaged mitochondria after controlled cortical impact, an in vivo model of traumatic brain injury (TBI). Here, we demonstrated that inhibition of mitophagy, the selective degradation of damaged mitochondria by autophagy, markedly enhanced inflammation induced by TBI. Melatonin treatment activated mitophagy through the mTOR pathway, then to attenuate TBI‐induced inflammation. Furthermore, treatment with melatonin significantly ameliorated neuronal death and behavioral deficits after TBI, while 3‐methyladenine reversed this effect by inhibiting mitophagy. Taken together, these results highlight a role for melatonin in protecting against TBI‐triggered immunopathology, which is accomplished by negatively regulating inflammation activation and IL‐1β secretion via the autophagy of damaged mitochondria.     

运动诱导的microRNA与心肌梗死的研究进展

运动使心血管系统获益众多,目前已将运动作为心肌梗死的重要治疗措施之一。由于运动调节心肌梗死（MI）的复杂性,其具体机制仍未完全阐明。近年来发现运动过程中多种微小RNAs（microRNAs,miRNAs）的表达发生改变,并且进一步发现运动诱导的miRNAs在MI病程中发挥重要作用。因此,本文重点总结基于运动调控下对于MI产生调节作用的miRNAs并分析其可能机制,旨在为运动训练对心肌梗死的临床应用提供更深入的理论依据。