与神经退行性疾病相关的RNA结合蛋白在线粒体损伤中的作用

线粒体是细胞内制造能量的细胞器,它还负责各种细胞信号的整合,参与协调多种复杂的细胞功能.线粒体是动态变化的,连续不断地进行分裂与融合,这是其功能维持和增殖遗传的关键.在过去20年中,参与线粒体分裂与融合的核心因子陆续被发现,它们在进化上高度保守,但是在形成分裂与融合复合物中的详细分子机制还有待于深入研究.线粒体分裂与融合的动态变化,是线粒体质量控制的重要组成部分,其动态平衡在细胞发育和稳态维持中起重要作用.线粒体动态变化失衡和功能失调,则会导致多种神经退行性疾病的发生.这些研究的发现为探索线粒体生物学及与疾病的关系开拓了令人振奋的新方向.     

简述调控线粒体形态变化的分子机制

线粒体是细胞内高度动态变化的细胞器,其在细胞内不断运动、融合、分裂并形成动态平衡的网状结构。线粒体的融合和分裂是由多种蛋白精确调控完成。Mfns／Fz01P控制线粒体外膜的融合,而Mgmlp／OPA1则参与线粒体内膜的融合;Dnm1p／Drp1、Fis1p／Fis1和Mdv1p介导线粒体分裂的调控。线粒体形态对于细胞维持正常生理代谢和机体发育起着重要的作用,一旦调控出现障碍会导致严重的疾病。     

线粒体分裂、融合与细胞凋亡

线粒体是高度动态变化的细胞器,其在细胞内不断分裂、融合并形成网状结构。线粒体的分裂和融合是由多种蛋白质精确调控完成的。Drp1／Dnm1p,Fis1／Fis1p,Caf4p和Mdv1p参与线粒体分裂的调控;Mfn1／2／Fzo1p控制线粒体外膜的融合,而Mgm1p／OPA1则参与线粒体内膜的融合。在细胞凋亡过程中线粒体片段化,网状结构被破坏,线粒体嵴发生重构,抑制这一过程可以部分抑制细胞色素c的释放和细胞凋亡。线粒体形态对于细胞维持正常生理代谢和机体发育起着重要的作用,一旦出现障碍会导致严重的疾病。     

Visualization of Mitochondrial Membrane Dynamics in Primary Cultured Neurons by Cryo-electron Tomography

本文利用冷冻电子断层扫描成像技术研究了原代培养海马神经元中线粒体膜的动态变化. 线粒体的分裂与融合是线粒体膜动态变化的主要方式，也是维持线粒体功能正常的重要手段. 线粒体分裂的机制研究以往是基于荧光标记的光学显微成像，由于分辨率的限制并不能直接观察到线粒体分裂过程中的超微结构特征. 冷冻电子断层成像通过尽可能保持样品生理状态从而获得更真实的结构信息. 本文通过对原代海马神经元中的自发性线粒体膜动态变化的成像，发现中央分裂和外周分裂的线粒体都与内质网在空间上存在一定的相互作用，内质网通过缠绕在线粒体分裂位点来参与分裂过程. 值得注意的是，还发现部分线粒体会出现线粒体外膜与内膜分离的现象，形成“无基质”的特殊区域. 这些可能都表明了线粒体质量控制的方式.     

线粒体融合与分裂在中枢神经系统疾病中的研究进展

线粒体是一种高度动态的细胞器,通过不断的融合和分裂维持其动态平衡,参与生理病理功能调节。线粒体融合与分裂主要由融合分裂相关蛋白调控,如Drp1、Fis1、Mfn1、Mfn2、OPA1等,多种诱导因子通过调节线粒体融合分裂相关蛋白表达及活化进而调节线粒体形态和生理功能。现有研究表明线粒体融合分裂的异常可能是许多中枢神经系统疾病的发病机制之一。本文从线粒体融合分裂的分子调控机制及其在缺血性脑中风、帕金森综合征和阿尔兹海默症等中枢神经系统疾病中的研究进展方面进行综述,为相关疾病的防治提供一定参考和线索。     

线粒体融合蛋白Mfn1/2的结构和功能

线粒体融合素基因（mitofusin gene,Mfn）在哺乳动物中编码两种蛋白质分子,Mfn1和Mfn2,它们在线粒体融合、分裂与细胞凋亡中起重要作用,调控着线粒体形态的动态变化。另外,Mfn1/2还参与线粒体的能量代谢并与相关疾病的发生有着密切关系。     

线粒体动力学调控机制及其在肾脏病理生理学中的作用

线粒体是一种动态变化的细胞器,它通过不断的融合、分裂来维持线粒体的形态、数量和功能稳定,这一过程称为线粒体动力学,是线粒体质量控制的重要机制。线粒体的过度融合与分裂都会导致线粒体动力学的稳态失衡,引起线粒体功能障碍,导致细胞损伤甚至死亡。肾脏的生理活动主要由线粒体供能,线粒体动力学稳态失衡影响着线粒体功能,与急性肾损伤、糖尿病肾病等肾脏疾病密切相关。本文对线粒体动力学的调节、线粒体动力学稳态失衡如何导致线粒体损伤以及线粒体损伤对肾脏病理生理学的影响进行综述,以加深对肾脏疾病中线粒体作用的理解与认识。     

线粒体动力学及线粒体自噬调控机制的研究进展

线粒体形态和功能的异常与多种疾病的发生密切相关。线粒体通过不断的分裂和融合,维持线粒体网络的动态平衡,该过程称为线粒体动力学,是维持线粒体形态、分布和数量,保证细胞稳态的重要基础。此外,机体还通过线粒体自噬过程降解胞内功能异常的线粒体,维持线粒体稳态。线粒体动力学与线粒体自噬二者之间可相互调控,共同维持线粒体质量平衡。探讨线粒体动力学和线粒体自噬的调控机制对揭示多种疾病发生的分子机制、开发新的靶向线粒体动力学蛋白或线粒体自噬调控蛋白的药物具有重要意义。本文从线粒体动力学与线粒体自噬出发,对线粒体动力学调控机制、线粒体自噬及其发生机制以及二者的相互作用关系、线粒体动力学及线粒体自噬与人类相关疾病等方面作一综述。     

线粒体融合/分裂对线粒体的质量控制作用

线粒体是一种结构和功能复杂而敏感的细胞器,拥有独立于细胞核的基因组,在细胞的不同时相,生理过程和环境条件下,线粒体的形态,数量和质量,具有高度的可塑性。线粒体是细胞和生物体内最主要的能量供应场所,几乎存在于所有种类的细胞中,是一种动态变化的细胞器。正常情况下,线粒体的数量、形态以及功能维持相对稳定的状态,称之为线粒体稳态。当上述状态发生紊乱时,细胞乃至生物体形态、功能也将受到影响甚至死亡。线粒体质量控制是在细胞中维持正常状态的关键机制,决定着线粒体的命运。近年,随着线粒体研究的深入和具体,逐渐发现融合/分裂在其形态、数量、遗传物质等质量控制相关的方面挥了重要作用。本文通过探讨融合/分裂对线粒体质量控制的作用机制,总结和讨论相关前沿研究,为后期研究提供一定的理论依据。     

泛素特异性蛋白酶30在线粒体动力学和自噬中的作用研究进展

线粒体作为细胞的能量中心,在细胞内呈现高度的动态变化,其数量、质量及功能的稳定对维持细胞的正常活动至关重要。线粒体动力学与线粒体自噬之间可互相调控,共同构成线粒体质量控制的重要环节。泛素特异性蛋白酶30 (USP30)作为去泛素化酶,既可通过线粒体融合蛋白1/2 (Mfn1/2)、线粒体动力蛋白相关蛋白1 (Drp1)等融合与分裂蛋白参与调控线粒体动力学过程,还能通过E3泛素连接酶Parkin、泛素(Ub)及电压依赖性阴离子通道1 (VDAC1)等多种信号而调控PTEN诱导激酶1 (PINK1)/Parkin途径介导的线粒体自噬,但其详细机制尚未完全阐明。本文对USP30在调控线粒体动力学和线粒体自噬中的作用与其机制进行了综述。     

线粒体动力学改变在神经变性疾病中的地位

线粒体是一种处于高度运动状态的细胞器,频繁地出现分裂和融合,线粒体分裂和融合的动态过程被称为线粒体动力学。对于神经元来说,线粒体的动力学过程具有十分重要的生物学意义。已知线粒体融合介导蛋白的功能缺失性突变可以导致常染色体显性遗传性视神经萎缩和Charcot-Marie-Tooth病等神经变性疾病。近来发现,在迟发性神经变性疾病中,线粒体动力学的改变也具有重要地位。本文将在线粒体动力学的分子调控以及与细胞死亡的关系、在神经变性疾病中的地位等方面综述这一领域的最新进展。     

Mitochondrial fusion and fission in cell life and death

Mitochondria are dynamic organelles that constantly fuse and divide. These processes (collectively termed mitochondrial dynamics) are important for mitochondrial inheritance and for the maintenance of mitochondrial functions. The core components of the evolutionarily conserved fusion and fission machineries have now been identified, and mechanistic studies have revealed the first secrets of the complex processes that govern fusion and fission of a double membrane-bound organelle. Mitochondrial dynamics was recently recognized as an important constituent of cellular quality control. Defects have detrimental consequences on bioenergetic supply and contribute to the pathogenesis of neurodegenerative diseases. These findings open exciting new directions to explore mitochondrial biology.     

Molecular mechanisms and physiologic functions of mitochondrial dynamics

Mitochondria are highly dynamic organelles that continuously change their shape through frequent fusion, fission and movement throughout the cell, and these dynamics are crucial for the life and death of the cells as they have been linked to apoptosis, maintenance of cellular homeostasis, and ultimately to neurologic disorders and metabolic diseases. Over the past decade, a growing number of novel proteins that regulate mitochondrial dynamics have been discovered. Large GTPase family proteins and their regulators control these aspects of mitochondrial dynamics. In this review, we briefly summarize the current knowledge about molecular machineries regulating mitochondrial fusion/fission and the role of mitochondrial dynamics in cell pathophysiology.     

Mitochondrial morphology and dynamics: actors, mechanisms and functions

Mitochondria are dynamic organelles that continuously move, fuse and divide. Their overall morphology, ranging from a filamentous network to a collection of isolated dots, is determined by fusion-fission equilibrium, which depends on the cellular and physiological context. The machineries of fusion and fission, that are conserved throughout evolution, include three large GTPases of the dynamin-superfamily: Dnm1/DRP1 - involved in fission?- as well as Fzo1/MFN and Mgm1/OPA1?- required for fusion. While the activities, mecanisms and regulations of mitochondrial fusion and fission machineries continue to be unravelled, the relevance of mitochondrial dynamics is witnessed by their impact on organelle functions, cell survival and cell differenciation, their requirement for embryonic development and their involvement in neurological diseases.     

Structure,function, and regulation of mitofusin‐2 in health and disease

Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin‐related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non‐neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression.     

Mitochondrial fission and fusion dynamics: the long and short of it

Maintenance of functional mitochondria requires fusion and fission of these dynamic organelles. The proteins that regulate mitochondrial dynamics are now associated with a broad range of cellular functions. Mitochondrial fission and fusion are often viewed as a finely tuned balance within cells, yet an integrated and quantitative understanding of how these processes interact with each other and with other mitochondrial and cellular processes is not well formulated. Direct visual observation of mitochondrial fission and fusion events, together with computational approaches promise to provide new insight.     

Endoplasmic reticulum stress induced by turbulence of mitochondrial fusion and fission was involved in stressed cardiomyocyte injury

Mitochondria are sensitive organelles that sense intrinsic and extrinsic stressors and maintain cellular physiological functions through the dynamic homeostasis of mitochondrial fusion and fission. Numerous pathological processes are associated with mitochondrial fusion and fission disorders. However, the molecular mechanism by which stress induces cardiac pathophysiological changes through destabilising mitochondrial fusion and fission is unclear. Therefore, this study aimed to investigate whether the endoplasmic reticulum stress signalling pathway initiated by the turbulence of mitochondrial fusion and fission under stressful circumstances is involved in cardiomyocyte damage. Based on the successful establishment of the classical stress rat model of restraint plus ice water swimming, we measured the content of serum lactate dehydrogenase. We used haematoxylin–eosin staining, special histochemical staining, RT-qPCR and western blotting to clarify the cardiac pathology, ultrastructural changes and expression patterns of mitochondrial fusion and fission marker proteins and endoplasmic reticulum stress signalling pathway proteins. The results indicated that mitochondrial fusion and fission markers and proteins of the endoplasmic reticulum stress JNK signalling pathway showed significant abnormal dynamic changes with the prolongation of stress, and stabilisation of mitochondrial fusion and fission using Mdivi-1 could effectively improve these abnormal expressions and ameliorate cardiomyocyte injury. These findings suggest that stress could contribute to pathological cardiac injury, closely linked to the endoplasmic reticulum stress JNK signalling pathway induced by mitochondrial fusion and fission turbulence.     

Mitochondrial dynamics and disease, OPA1

The mitochondria are dynamic organelles that constantly fuse and divide. An equilibrium between fusion and fission controls the morphology of the mitochondria, which appear as dots or elongated tubules depending the prevailing force. Characterization of the components of the fission and fusion machineries has progressed considerably, and the emerging question now is what role mitochondrial dynamics play in mitochondrial and cellular functions. Its importance has been highlighted by the discovery that two human diseases are caused by mutations in the two mitochondrial pro-fusion genes, MFN2 and OPA1. This review will focus on data concerning the function of OPA1, mutations in which cause optic atrophy, with respect to the underlying pathophysiological processes.     

TRAP1 Controls Mitochondrial Fusion/Fission Balance through Drp1 and Mff Expression

Mitochondria are dynamic organelles that change in response to extracellular stimuli. These changes are essential for normal mitochondrial/cellular function and are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Although some molecules have been identified to mediate the mitochondrial fusion and fission process, the underlying mechanisms remain unclear. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecule that regulates a variety of mitochondrial functions. Here, we examined the role of TRAP1 in the regulation of morphology. Stable TRAP1 knockdown cells showed abnormal mitochondrial morphology, and we observed significant decreases in dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff), mitochondrial fission proteins. Similar results were obtained by transient knockdown of TRAP1 in two different cell lines, SH-SY5Y neuroblastoma cells and KNS-42 glioma cells. However, TRAP1 knockdown did not affect expression levels of fusion proteins. The reduction in Drp1 and Mff protein levels was rescued following treatment with the proteasome inhibitor MG132. These results suggest that TRAP1 regulates the expression of fission proteins and controls mitochondrial fusion/fission, which affects mitochondrial/cellular function.     

The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease

Mitochondria play critical roles in neuronal function and almost all aspects of mitochondrial function are altered in Alzheimer neurons. Emerging evidence shows that mitochondria are dynamic organelles that undergo continuous fission and fusion, the balance of which not only controls mitochondrial morphology and number, but also regulates mitochondrial function and distribution. In this review, after a brief overview of the basic mechanisms involved in the regulation of mitochondrial fission and fusion and how mitochondrial dynamics affects mitochondrial function, we will discuss in detail our and others' recent work demonstrating abnormal mitochondrial morphology and distribution in Alzheimer's disease (AD) models and how these abnormalities may contribute to mitochondrial and synaptic dysfunction in AD. We propose that abnormal mitochondrial dynamics plays a key role in causing the dysfunction of mitochondria that ultimately damage AD neurons.