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。     

线粒体形态学改变与细胞凋亡

近年来,对于线粒体形态学以及其在凋亡过程中的改变和作用的研究打破了传统的观点。正常情况下,线粒体在细胞内相互连接成管网状结构,并发生着频繁的融合与分裂。融合和分裂由一系列蛋白质介导,二者之间的动态平衡维持着线粒体的形态和功能。在细胞凋亡的早期,线粒体融合和分裂失平衡,导致线粒体管网状结构碎裂和嵴的重构,这些改变对线粒体随后的变化以及凋亡的发生具有重要的意义。融合和分裂的蛋白质不仅调控线粒体形态和细胞凋亡过程,也和某些凋亡相关疾病有关。此外,促凋亡的Bcl-2蛋白可能通过改变线粒体的构形来调控凋亡过程。     

哺乳动物细胞线粒体融合-分裂与钙离子信号的关系

线粒体是一种高度动态的细胞器,通过融合和分裂两个相反的过程来维持正常的形态结构。在哺乳动物中,多种因素影响线粒体的融合-分裂的平衡,但现已明确,线粒体融合的主要调节因子为Mfn1/2、OPA1,介导线粒体分裂的主要调节因子为Drp1、Fis1。新近研究发现,线粒体融合-分裂平衡的紊乱将导致线粒体结构和在细胞内分布的异常,进而影响细胞和线粒体对钙离子信号的反应;同时,钙离子也可通过多种机制影响线粒体的形态结构与分布。     

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。     

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.     

线粒体分裂和融合相关蛋白质的研究进展

线粒体是多细胞生物的一个重要组成部分,它对细胞以及机体的健康具有十分重要的作用。线粒体可以产生能量,介导钙和活性氧信号转导,甚至调控细胞凋亡。近年来研究显示,线粒体在细胞中处于不断分裂与融合的状态,并且可以在细胞内重新分布,线粒体的这种特性统称为线粒体动力学。线粒体动力学对维持线粒体各种功能极其重要,成为了近年来的研究热点。本文重点综述了哺乳动物细胞内线粒体分裂和融合相关蛋白质的结构以及生物学功能。     

缺血性心脏病的线粒体质量控制及迷走神经干预

缺血性心脏病(ischemic heart disease,IHD)是危害人类健康的首要疾病。线粒体是细胞内能量供应和信息整合的中心,决定细胞的生存和/或死亡。线粒体质量控制是指线粒体分裂与融合、线粒体自噬等动态调节过程。新近研究显示,增强线粒体质量控制对维持线粒体健康以及心肌功能至关重要,而线粒体质量控制任何一个环节的紊乱都将导致心肌缺血损伤的发生和发展。本文就线粒体质量控制及其在IHD中的研究进展作一综述,并结合本实验室研究成果,阐述迷走神经干预改善IHD的线粒体质量控制相关机制。     

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。     

线粒体质量控制失调与恶性肿瘤发生和发展相关性的研究进展

线粒体活性氧增多、线粒体DNA突变和拷贝数改变、Ca~(2+)超载、凋亡异常等功能障碍与肿瘤发生、生长、侵袭、转移密切相关.随着研究的逐渐深入,人们认识到线粒体是个动态的细胞器,在生理、病理因素刺激下,经线粒体融合/分裂、线粒体自噬、线粒体生物合成以及线粒体分子伴侣和线粒体未折叠蛋白反应的协同调控,在细胞器和分子水平达到对线粒体及其蛋白质的质量控制,限制和延缓功能受损线粒体的积累和过度增多,维持线粒体数量、形态、功能和蛋白质量的动态平衡,保证细胞正常生命活动的进行,使其更好地适应环境.若线粒体及其蛋白的稳态调节能力下降或失衡,会导致受损线粒体的积累并引发细胞内环境的紊乱,影响线粒体功能的正常发挥,从而诱导正常细胞的恶性转化.     

线粒体质量控制与米色脂肪之间的关系

近年来,肥胖患病率不断上升,肥胖已成为全球性公共卫生问题.肥胖能够增加高血压、冠心病等心血管疾病的发病风险,防治肥胖已经成为亟待解决的社会问题.米色脂肪是一种产热型脂肪细胞,可在受到寒冷、药物、运动等外界刺激下由白色脂肪细胞转化而来,但其形态和功能却与白色脂肪细胞不同,而与棕色脂肪细胞类似,即米色脂肪同样含有丰富的线粒...     

Mitochondrial quality control in stroke: From the mechanisms to therapeutic potentials

Mitochondrial damage is a critical contributor to stroke‐induced injury, and mitochondrial quality control (MQC) is the cornerstone of restoring mitochondrial homeostasis and plays an indispensable role in alleviating pathological process of stroke. Mitochondria quality control promotes neuronal survival via various adaptive responses for preserving mitochondria structure, morphology, quantity and function. The processes of mitochondrial fission and fusion allow for damaged mitochondria to be segregated and facilitate the equilibration of mitochondrial components such as DNA, proteins and metabolites. The process of mitophagy is responsible for the degradation and recycling of damaged mitochondria. This review aims to offer a synopsis of the molecular mechanisms involved in MQC for recapitulating our current understanding of the complex role that MQC plays in the progression of stroke. Speculating on the prospect that targeted manipulation of MQC mechanisms may be exploited for the rationale design of novel therapeutic interventions in the ischaemic stroke and haemorrhagic stroke. In the review, we highlight the potential of MQC as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.     

Optimal Dynamics for Quality Control in Spatially Distributed Mitochondrial Networks

Recent imaging studies of mitochondrial dynamics have implicated a cycle of fusion, fission, and autophagy in the quality control of mitochondrial function by selectively increasing the membrane potential of some mitochondria at the expense of the turnover of others. This complex, dynamical system creates spatially distributed networks that are dependent on active transport along cytoskeletal networks and on protein import leading to biogenesis. To study the relative impacts of local interactions between neighboring mitochondria and their reorganization via transport, we have developed a spatiotemporal mathematical model encompassing all of these processes in which we focus on the dynamics of a health parameter meant to mimic the functional state of mitochondria. In agreement with previous models, we show that both autophagy and the generation of membrane potential asymmetry following a fusion/fission cycle are required for maintaining a healthy mitochondrial population. This health maintenance is affected by mitochondrial density and motility primarily through changes in the frequency of fusion events. Health is optimized when the selectivity thresholds for fusion and fission are matched, providing a mechanistic basis for the observed coupling of the two processes through the protein OPA1. We also demonstrate that the discreteness of the components exchanged during fusion is critical for quality control, and that the effects of limiting total amounts of autophagy and biogenesis have distinct consequences on health and population size, respectively. Taken together, our results show that several general principles emerge from the complexity of the quality control cycle that can be used to focus and interpret future experimental studies, and our modeling framework provides a road-map for deconstructing the functional importance of local interactions in communities of cells as well as organelles.     

Mitochondrial Fission: Regulation and ER Connection

Fission and fusion of mitochondrial tubules are the main processes determining mitochondrial shape and size in cells. As more evidence is found for the involvement of mitochondrial morphology in human pathology, it is important to elucidate the mechanisms of mitochondrial fission and fusion. Mitochondrial morphology is highly sensitive to changing environmental conditions, indicating the involvement of cellular signaling pathways. In addition, the well-established structural connection between the endoplasmic reticulum (ER) and mitochondria has recently been found to play a role in mitochondrial fission. This minireview describes the latest advancements in understanding the regulatory mechanisms controlling mitochondrial morphology, as well as the ER-mediated structural maintenance of mitochondria, with a specific emphasis on mitochondrial fission.     

Mitochondrial Morphological Features Are Associated with Fission and Fusion Events

Mitochondria are dynamic organelles that undergo constant remodeling through the regulation of two opposing processes, mitochondrial fission and fusion. Although several key regulators and physiological stimuli have been identified to control mitochondrial fission and fusion, the role of mitochondrial morphology in the two processes remains to be determined. To address this knowledge gap, we investigated whether morphological features extracted from time-lapse live-cell images of mitochondria could be used to predict mitochondrial fate. That is, we asked if we could predict whether a mitochondrion is likely to participate in a fission or fusion event based on its current shape and local environment. Using live-cell microscopy, image analysis software, and supervised machine learning, we characterized mitochondrial dynamics with single-organelle resolution to identify features of mitochondria that are predictive of fission and fusion events. A random forest (RF) model was trained to correctly classify mitochondria poised for either fission or fusion based on a series of morphological and positional features for each organelle. Of the features we evaluated, mitochondrial perimeter positively correlated with mitochondria about to undergo a fission event. Similarly mitochondrial solidity (compact shape) positively correlated with mitochondria about to undergo a fusion event. Our results indicate that fission and fusion are positively correlated with mitochondrial morphological features; and therefore, mitochondrial fission and fusion may be influenced by the mechanical properties of mitochondrial membranes.     

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.     

膜蛋白ATAD3A在线粒体质量控制中的作用

线粒体质量控制对于线粒体网络的稳态和线粒体功能的正常发挥具有重要意义。三磷酸腺苷酶家族蛋白3A(ATAD3A)是同时参与调节线粒体结构功能、线粒体动力学和线粒体自噬等重要生物学过程的线粒体膜蛋白之一。近期研究表明,ATAD3A既可与Mic60/Mitofilin和线粒体转录因子A (TFAM)等因子相互作用以维持线粒体嵴的形态和氧化磷酸化功能,又能与发动蛋白相关蛋白1 (Drp1)结合而正性/负性调节线粒体分裂,还可作为线粒体外膜转位酶（TOM）复合物和线粒体内膜转位酶（TIM）复合物之间的桥接因子而介导PTEN诱导激酶（PINK1）输入线粒体进行加工,显示出促自噬或抗自噬活性。本文对ATAD3A在调控线粒体质量控制中的作用及其机制进行了综述。     

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.     

Mitochondrial fragmentation in excitotoxicity requires ROCK activation

Mitochondria morphology constantly changes through fission and fusion processes that regulate mitochondrial function, and it therefore plays a prominent role in cellular homeostasis. Cell death progression is associated with mitochondrial fission. Fission is mediated by the mainly cytoplasmic Drp1, which is activated by different post-translational modifications and recruited to mitochondria to perform its function. Our research and other studies have shown that in the early moments of excitotoxic insult Drp1 must be nitrosylated to mediate mitochondrial fragmentation in neurons. Nonetheless, mitochondrial fission is a multistep process in which filamentous actin assembly/disassembly and myosin-mediated mitochondrial constriction play prominent roles. Here we establish that in addition to nitric oxide production, excitotoxicity-induced mitochondrial fragmentation also requires activation of the actomyosin regulator ROCK. Although ROCK1 has been shown to phosphorylate and activate Drp1, experiments using phosphor-mutant forms of Drp1 in primary cortical neurons indicate that in excitotoxic conditions, ROCK does not act directly on Drp1 to mediate fission, but may act on the actomyosin complex. Thus, these data indicate that a wider range of signaling pathways than those that target Drp1 are amenable to be inhibited to prevent mitochondrial fragmentation as therapeutic option.     

Mitochondrial functional complementation in mitochondrial DNA-based diseases

Mitochondria exist in networks that are continuously remodeled through fusion and fission. Why do individual mitochondria in living cells fuse and divide continuously? Protein machinery and molecular mechanism for the dynamic nature of mitochondria have been almost clarified. However, the biological significance of the mitochondrial fusion and fission events has been poorly understood, although there is a possibility that mitochondrial fusion and fission are concerned with quality controls of mitochondria. trans-mitochondrial cell and mouse models possessing heteroplasmic populations of mitochondrial DNA (mtDNA) haplotypes are quite efficient for answering this question, and one of the answers is “mitochondrial functional complementation” that is able to regulate respiratory function of individual mitochondria according to “one for all, all for one” principle. In this review, we summarize the observations about mitochondrial functional complementation in mammals and discuss its biological significance in pathogeneses of mtDNA-based diseases.