线粒体移植治疗心血管疾病研究进展

心血管疾病的发病率和死亡率逐年升高,且在世界范围内的疾病负担中占据首位。线粒体功能异常可引起细胞到组织的病变,多种心血管疾病被证实与线粒体功能障碍有关。线粒体移植(mitochondria transplantation, MTP)是一种新兴的治疗手段,用于治疗因线粒体功能障碍引起的组织损伤。经过十多年从基础实验到临床试验的发展,MTP在心血管疾病中的治疗作用逐渐被证实,并且备受关注。该文就MTP的研究基础及其在心血管疾病中的研究进展进行综述。     

线粒体囊泡调控机制与生理功能研究进展

线粒体在细胞的生命活动过程中承担重要作用,线粒体通过自身质量控制维持线粒体健康.线粒体囊泡作为一种新型的线粒体质量控制机制,通过靶向到不同的细胞器,调控线粒体内氧化/受损蛋白的降解;激活免疫系统,发挥抗原呈递和杀灭细菌的功能,从而维持线粒体以及细胞的稳态平衡.本文就线粒体囊泡的调控机制以及生物学功能的研究进展进行综述.     

线粒体蛋白酶与人类疾病

线粒体是真核细胞的重要细胞器,在能量转换、细胞应激、脂质合成以及细胞凋亡中具有调节作用.许多线粒体蛋白酶参与蛋白质运输、加工激活和降解过程.其中, ATP依赖性的线粒体蛋白酶通过其AAA+结构域(ATP associated multiple activity domain, AAA domain)利用ATP水解来执行线粒体蛋白质质量控制和调节蛋白降解.线粒体蛋白酶活性的改变会导致线粒体功能障碍,从而导致多种人类疾病,包括心血管疾病、神经退行性疾病、衰老和肿瘤等.本文重点综述线粒体蛋白酶1(Lon protease 1, LONP1)、酪蛋白水解蛋白酶P(caseinolytic protease, ClpP)、m-AAA(IMM-embedded AAA face to matrix)和i-AAA(IMM-embedded AAA face to intermembrane space)蛋白酶四种ATP依赖性线粒体蛋白酶及其功能,并阐述其与人类疾病的相关性和临床意义.     

线粒体DNA病

线粒体ＤＮＡ病王学敏杨雨善谢惠君郑惠民（第二军医大学,上海２００４３３）关键词线粒体病线粒体ＤＮＡ近年确认了线粒体ＤＮＡ（ｍｔＤＮＡ）突变会引起人类疾病,临床症状有盲、聋、痴呆、运动障碍、肌肉衰弱、心力衰竭、糖尿病、肾功能不全、肝病等。ｍｔＤＮＡ呈裸...     

线粒体结构和功能改变对阿尔茨海默病发生的影响

阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性认知障碍和行为损害为主要特征的神经退行性疾病,主要临床表现为认知功能障碍,同时伴发精神障碍和情绪障碍.AD患者脑中早期即表现出细胞内线粒体功能紊乱和结构变化,纠正线粒体稳态失衡及由其引起的细胞病理改变可能是早期治疗AD的潜在靶点.该文主要对线粒体...     

细胞间线粒体转运的研究进展

线粒体是真核生物能量代谢的重要细胞器,是细胞进行氧化磷酸化生成ATP的主要场所.他参与完成细胞能量代谢、维持离子浓度梯度、传递细胞凋亡信号等生理功能.阿尔茨海默病、帕金森病、心肌梗塞等疾病与线粒体功能异常相关.近年来发现,由创伤或炎症造成脑、心脏、肺缺氧时在细胞间会发生线粒体转移.线粒体转移,作为一种进化上保守的现象可能与神经降解、心血管疾病等相关.     

植物细胞质雄性不育分子机理研究进展

本文从线粒体基因组、线粒体基因、线粒体转录 RNA、 线粒体蛋白、转基因植物以及花粉败育机理六个方面详细介绍了植物细胞质雄性不育分子生物学研究的技术和方法。综述了植物细胞质雄性不育分子机理研究的进展,并对植物细胞质雄性不育分子机理的前景作了展望。     

线粒体单体型与线粒体相关的人类疾病

线粒体是一种拥有自身遗传体系的半自主细胞器,它的遗传物质线粒体DNA(mitochondrial DNA,mt DNA)随着人类的迁移、隔离、进化而形成了广泛的线粒体基因组多态性,同一祖先所具有的一些相同mt DNA SNP位点的集合称为线粒体单体型.不同的线粒体单体型会在一定程度上影响线粒体功能,从而影响整个细胞的生长,并在某些情况下导致一些个体的病变,例如Leber遗传性视神经病变、母系遗传性耳聋、Ⅱ型糖尿病、帕金森以及各种癌症等复杂疾病.本文列举总结了几种线粒体相关疾病及其与线粒体单体型如A、B、D、F、G、H、J、K、M、N、T、U、Y及一些有特点的多态位点如G11778A、A1555G、T3394C、G10398A等的相关性.     

A Comparative Characterization of the Mitochondrial Genomes of Paramoeba aparasomata and Neoparamoeba pemaquidensis (Amoebozoa,Paramoebidae)

Marine amebae of the genus Paramoeba (Amoebozoa, Dactylopodida) normally contain a eukaryotic endosymbiont known as Perkinsela‐like organism (PLO). This is one of the characters to distinguish the genera Neoparamoeba and Paramoeba from other Dactylopodida. It is known that the PLO may be lost, but PLO‐free strains of paramoebians were never available for molecular studies. Recently, we have described the first species of the genus Paramoeba which has no parasome—Paramoeba aparasomata. In this study, we present a mitochondrial genome of this species, compare it with that of Neoparamoeba pemaquidensis, and analyze the evolutionary dynamics of gene sequences and gene order rearrangements between these species. The mitochondrial genome of P. aparasomata is 46,254 bp long and contains a set of 31 protein‐coding genes, 19 tRNAs, two rRNA genes, and 7 open reading frames. Our results suggest that these two mitochondrial genomes within the genus Paramoeba have rather similar organization and gene order, base composition, codon usage, the composition and structure of noncoding, and overlapping regions.     

Isolation of a cDNA clone encoding mouse 3-hydroxyacyl CoA dehydrogenase

Rae-38, a cDNA clone isolated from mouse embryonal carcinoma F9 cells, was sequenced, and the deduced RAE-38 protein showed about 86% homology to pig 3-hydroxyacyl CoA dehydrogenase (HCDH; EC 1.1.1.35). This clone can be used to elucidate the regulatory mechanism of HCDH gene expression in mammals.     

神经退行性疾病的早期信号:线粒体功能障碍

线粒体是广泛存在于各种真核细胞中,可以进行独立复制的特殊的细胞器,它既能提供细胞内各种生命活动所需要的能源,也参与多种其他极为重要的生理活动。线粒体呼吸功能的障碍是许多神经退行性疾病发病早期共识的病理现象,探索线粒体在疾病发生过程中的变化,不仅对研究AD等神经退行性疾病的发病机理,对设计和开发创新药物也具有重要的指导意义。本文就线粒体的结构功能及其在神经退行性疾病发病过程中出现功能障碍的证据、诱因和可能的治疗方案作一简要综述。     

Effects of disruption of the mitochondrial electrochemical gradient on steroidogenesis and the Steroidogenic Acute Regulatory (StAR) proteinProceedings of Xth International Congress on Hormonal Steroids, Quebec, Canada, 17–21 June 1998.

The steroidogenic acute regulatory (StAR) protein, which mediates cholesterol delivery to the inner mitochondrial membrane and the P450scc enzyme, has been shown to require a mitochondrial electrochemical gradient for its activity in vitro. To characterize the role of this gradient in cholesterol transfer, investigations were conducted in whole cells, utilizing the protonophore carbonyl cyanide m-chlorophenylhydrazone (m-CCCP) and the potassium ionophore valinomycin. These reagents, respectively, dissipate the mitochondrial electrochemical gradient and inner mitochondrial membrane potential. Both MA-10 Leydig tumor cell steroidogenesis and mitochondrial import of StAR were inhibited by m-CCCP or valinomycin at concentrations which had only minimal effects on P450scc activity. m-CCCP also inhibited import and processing of both StAR and the truncated StAR mutants, N-19 and C-28, in transfected COS-1 cells. Steroidogenesis induced by StAR and N-47, an active N-terminally truncated StAR mutant, was reduced in transfected COS-1 cells when treated with m-CCCP. This study shows that StAR action requires a membrane potential, which may reflect a functional requirement for import of StAR into the mitochondria, or more likely, an unidentified factor which is sensitive to ionophore treatment. Furthermore, the ability of N-47 to stimulate steroidogenesis in nonsteroidogenic HepG2 liver tumor cells, suggests that the mechanism by which StAR acts may be common to many cell types.     

In vitro studies on the role of the peripheral-type benzodiazepine receptor in steroidogenesis

In vitro studies using isolated cells, mitochondria and submitochondrial fractions demonstrated that in steroid synthesizing cells, the peripheral-type benzodiazepine receptor (PBR) is an outer mitochondrial membrane protein, preferentially located in the outer/inner membrane contact sites, involved in the regulation of cholesterol transport from the outer to the inner mitochondrial membrane, the rate-determining step in steroid biosynthesis. Mitochondrial PBR ligand binding characteristics and topography are sensitive to hormone treatment suggesting a role of PBR in the regulation of hormone-mediated steroidogenesis. Targeted disruption of the PBR gene in Leydig cells in vitro resulted in the arrest of cholesterol transport into mitochondria and steroid formation; transfection of the mutant cells with a PBR cDNA rescued steroidogenesis demonstrating an obligatory role for PBR in cholesterol transport. Molecular modeling of PBR suggested that it might function as a channel for cholesterol. This hypothesis was tested in a bacterial system devoid of PBR and cholesterol. Cholesterol uptake and transport by these cells was induced upon PBR expression. Amino acid deletion followed by site-directed mutagenesis studies and expression of mutant PBRs demonstrated the presence in the cytoplasmic carboxy-terminus of the receptor of a cholesterol recognition/interaction amino acid consensus sequence. This amino acid sequence may help for recruiting the cholesterol coming from intracellular sites to the mitochondria.     

Ageing and mammalian mitochondrial genetics

Mitochondrial DNA (mtDNA) is essential for the ability of mammalian cells to generate a functional oxidative phosphorylation system. Mutations in mtDNA occur in human disease and also during ageing. Here, we address three questions concerning the occurrence and accumulation of mtDNA mutations during the lifespan of the mammalian cell. What sort of mutations accumulate with age in humans and other mammals? How is the female germ line spared from the accumulation of such mutations as occurs in many somatic tissues, so that neonates normally start life with a ‘clean sheet'? Is the occurrence of mtDNA mutations associated with the functional decline of cells and tissues during ageing? We argue that mtDNA mutations in somatic cells do not just reflect a passive imprint of ageing, but they are causally associated with the loss of bioenergetic function during the ageing process.     

与人类疾病相关的几种线粒体氨基酰-tRNA合成酶

氨基酰-tRNA合成酶是一类古老的蛋白质,催化蛋白质生物合成中的第一步反应．已经发现氨基酰-tRNA合成酶还参与大量的其他生命过程,如编校、tRNA的成熟与转运、RNA的剪切、细胞因子等功能．最近的研究结果表明,线粒体氨基酰-tRNA合成酶与人类的疾病密切相关．人线粒体精氨酰-tRNA合成酶基因2号内含子中的一个单点突变导致该基因的转录本被异常剪接,造成脑桥小脑发育不全．人线粒体天冬氨酰-tRNA合成酶基因上的一系列突变致使其mRNA被快速降解或者蛋白质氨基酸一级结构的改变,导致脑干脊髓白质病变及乳糖增高症．人线粒体亮氨酰-tRNA合成酶基因的一个单核苷酸多态性与2型糖尿病密切相关．这些研究结果进一步增强了我们对于氨基酰-tRNA合成酶的生物学功能的认识,并将促进对由线粒体氨基酰-tRNA合成酶所引起线粒体病的致病机理以及治疗方法的研究．     

线粒体钙离子单向转运蛋白MCU及调节蛋白MICU1

线粒体钙离子摄入对能量生成、细胞分裂和死亡均具有十分重要的作用,但对该过程的机制却知之甚少。最近研究鉴定出线粒体钙离子单向转运蛋白(MCU,mitochondrial calcium uniporter)和线粒体钙离子摄入蛋白1(MICU1,mitochondrial calcium uptake 1),这两种蛋白都定位于线粒体内膜,均参与钙离子摄入。MCU拥有两个跨膜结构域,显示出钙离子通道活性并对钌红敏感,而MICU1具有两个典型的EF手形结构域,该结构可感知钙离子的变化,可能作为MCU调节蛋白发挥作用。这些研究进展对线粒体内稳态的理解和线粒体相关疾病的治疗具有重要意义。