转线粒体细胞模型

转线粒体细胞模型是由无线粒体DNA(mtDNA)细胞与mtDNA供体通过融合的方法而形成的融合细胞。随着转线粒体技术的发展,制备该细胞模型的方法也多种多样。现今,转线粒体模型的应用十分广泛,不仅可应用于线粒体相关疾病的基础研究,而且在线粒体相关疾病的临床研究中也发挥了重要的作用。融合细胞具有一致的核背景,可以消除核基因的作用,因而有助于判断mtDNA突变的致病作用及机制和线粒体缺陷的致病作用及机制。此外,利用该模型还可作为探讨线粒体相关疾病基因治疗和筛选疾病治疗药物的有效模型。     

线粒体疾病小鼠模型的建立及病理生理学研究

线粒体疾病是机体ATP合成障碍、供能不足引起的多系统疾病。近十年来,随着线粒体疾病小鼠模型的不断建立和完善,发现核DNA（nuclear DNA,nDNA）或（和）线粒体DNA（mitochondrial DNA,mtDNA）突变造成线粒体氧化磷酸化功能缺陷是其发病的主要原因。将着重介绍线粒体氧化磷酸化功能缺陷导致线粒体疾病的小鼠模型的建立及其病理生理学特点。     

线粒体DNA与DNA甲基化的关系

线粒体DNA（mitochondrial DNA,mtDNA）遗传信息量虽小,却控制着线粒体一些最基本的性质,对细胞及其功能有着重要影响。mtDNA的损伤与衰老、肿瘤等疾病的发生有关。DNA甲基化是调节基因表达的重要方式之一。mtDNA基因的表达受核DNA（nuclear DNA,nDNA）的调控,mtDNA和nDNA协同作用参与机体代谢调节和发病。本文就近年来mtDNA与DNA甲基化的关系作一综述。     

线粒体DNA与DNA甲基化

线粒体是除细胞核之外唯一携带遗传物质的细胞器,其线粒体DNA（mitochondrial DNA,mtDNA）控制着线粒体一些最基本的性质,对细胞功能有着重要影响.DNA甲基化是调节基因表达的重要方式之一.研究表明mtDNA存在CpG位点的低甲基化,并且mtDNA基因的表达受核DNA（nuclear DNA,nDNA）及线粒体自身DNA甲基化的调控,mtDNA和nDNA协同作用参与机体代谢调节和疾病发生发展过程.就近年来mtDNA与DNA甲基化的关系作一综述.     

线粒体DNA突变与肿瘤发生的关系

线粒体DNA（mitochondrial DNA,mtDNA）是真核细胞内的核外遗传物质。事实证明,由于线粒体特殊的生物学结构与功能,和核基因（nDNA）相比,mtDNA更容易发生突变和氧化损伤。目前研究已经发现许多肿瘤组织中mtDNA结构和拷贝量发生了变化。文章主要对mtDNA突变、整合和不稳定性与肿瘤发生的关系以及可能的机理进行了综述。     

线粒体病的基因治疗

线粒体病是一组因线粒体DNA缺失或突变而致氧化磷酸化及能量供应异常的疾病,目前该类疾病的治疗主要是支持治疗。然而由于线粒体结构和功能的特殊性,该疗效并不确切。因此,线粒体病的基因治疗显得越来越迫切和重要。目前,基因治疗的策略包括降低突变型mtDNA／野生型mtDNA的比例、错位表达、输入其他同源性基因以及利用限制性内切酶修复突变型mtDNA等。     

高血压相关的线粒体DNA突变

线粒体DNA(mtDNA)突变是高血压发病的分子机制之一。已经报道的与原发性高血压相关的mtDNA突变包括:tRNAMet A4435G,tRNAMet/tRNAGln A4401G,tRNAIle A4263G,T4291C和A4295G突变。这些高血压相关的mtDNA突变改变了相应的线粒体tRNA的结构,导致线粒体tRNA的代谢障碍。而线粒体tRNAs的代谢缺陷则影响蛋白质合成,造成氧化磷酸化缺陷,降低ATP的合成,增加活性氧的产生。因此,线粒体的功能缺陷可能在高血压的发生发展中起一定的作用。mtDNA突变发病的组织特异性则可能与线粒体tRNAs的代谢以及核修饰基因相关。目前发现的这些高血压相关的mtDNA突变则应该作为今后高血压诊断的遗传风险因子。高血压相关的线粒体功能缺陷的深入研究也将进一步诠释母系遗传高血压的分子致病机制,为高血压的预防、控制和治疗提供依据。文章对高血压相关的mtDNA突变进行了综述。     

线粒体DNA突变与相关人类疾病

在过去的20年里, 人们发现线粒体DNA(mitochondrial DNA, mtDNA)突变与多种人类疾病相关, 其致病范围从单器官组织损害到多系统受累。文章目的在于探讨mtDNA突变与人类疾病的关系。文章重点论述: (1)线粒体遗传学特征; (2) mtDNA突变与人类遗传性疾病; (3)体细胞mtDNA突变在衰老和肿瘤中的作用; (4)mtDNA疾病的诊断和治疗。     

线粒体基因突变与糖尿病的相关性研究进展

线粒体DNA(mtDNA)突变可引起多种遗传性疾病,其中包括糖尿病.与mtDNA突变相关的糖尿病中最常见的变异是tRNALeu(UUR)] 3243 A→G.文章描述了mtDNA线粒体突变与糖尿病的相关性,介绍了线粒体糖尿病的临床特点和发病机制,概括了线粒体糖尿病相关变异基因位点,重点介绍了m.3243A→G、3310C→T、16189T→C基因突变与线粒体糖尿病病理生理的联系.文章认为mtDNA突变位点的研究为糖尿病的发生机制提供新的视角,也为糖尿病的治疗提供了新方向.     

线粒体DNA异质性

线粒体 DNA（mitochondrial DNA,mtDNA）是线粒体内最重要的遗传物质。mtDNA 突变普 遍存在,突变型 mtDNA 与野生型 mtDNA 共存的现象被称为 mtDNA 异质性。mtDNA 异质性与衰老和多种疾病密切相关。mtDNA异质性特性、mtDNA 异质性与衰老和疾病相关性以及线粒体疾病的治疗等都是近年来遗传学研究的热点。本文从 mtDNA 异质性的动态变化、组织特异性、mtDNA 异质性与疾病以及线粒体疾病的治疗等方面对 mtDNA 异质性进行综述。     

Nuclear genes and mitochondrial translation: a new class of genetic disease

Mitochondria contain a separate protein-synthesis machinery to produce the polypeptides encoded in mitochondrial DNA (mtDNA), and many mtDNA disease mutations affect this machinery. In humans, the mitochondrial rRNAs and tRNAs are encoded by mtDNA, whereas all proteins involved in mitochondrial translation are encoded by nuclear genes. Recently, several articles have discussed the identification of pathological mutations in nuclear genes encoding components of this protein-synthesis machinery, suggesting that these types of mutation are a frequent cause of human genetic diseases.     

Mouse models of mitochondrial DNA defects and their relevance for human disease

Qualitative and quantitative changes in mitochondrial DNA (mtDNA) have been shown to be common causes of inherited neurodegenerative and muscular diseases, and have also been implicated in ageing. These diseases can be caused by primary mtDNA mutations, or by defects in nuclear‐encoded mtDNA maintenance proteins that cause secondary mtDNA mutagenesis or instability. Furthermore, it has been proposed that mtDNA copy number affects cellular tolerance to environmental stress. However, the mechanisms that regulate mtDNA copy number and the tissue‐specific consequences of mtDNA mutations are largely unknown. As post‐mitotic tissues differ greatly from proliferating cultured cells in their need for mtDNA maintenance, and as most mitochondrial diseases affect post‐mitotic cell types, the mouse is an important model in which to study mtDNA defects. Here, we review recently developed mouse models, and their contribution to our knowledge of mtDNA maintenance and its role in disease.     

Defects in mitochondrial DNA replication and human disease

Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase g in concert with accessory proteins such as the mtDNA helicase, single stranded DNA binding protein, topoisomerase, and initiating factors. Nucleotide precursors for mtDNA replication arise from the mitochondrial salvage pathway originating from transport of nucleosides, or alternatively from cytoplasmic reduction of ribonucleotides. Defects in mtDNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mtDNA deletions, point mutations, or depletion which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mtDNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders, such as progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). This review focuses on our current knowledge of genetic defects of mtDNA replication (POLG, POLG2, C10orf2) and nucleotide metabolism (TYMP, TK2, DGOUK, and RRM2B) that cause instability of mtDNA and mitochondrial disease.     

Involvement of autophagy and mitochondrial dynamics in determining the fate and effects of irreparable mitochondrial DNA damage

Mitochondrial DNA (mtDNA) is different in many ways from nuclear DNA. A key difference is that certain types of DNA damage are not repaired in the mitochondrial genome. What, then, is the fate of such damage? What are the effects? Both questions are important from a health perspective because irreparable mtDNA damage is caused by many common environmental stressors including ultraviolet C radiation (UVC). We found that UVC-induced mtDNA damage is removed slowly in the nematode Caenorhabditis elegans via a mechanism dependent on mitochondrial fusion, fission, and autophagy. However, knockdown or knockout of genes involved in these processes—many of which have homologs involved in human mitochondrial diseases—had very different effects on the organismal response to UVC. Reduced mitochondrial fission and autophagy caused no or small effects, while reduced mitochondrial fusion had dramatic effects.     

Multifactorial nature of high frequency of mitochondrial DNA mutations in somatic mammalian cells

The high frequency of mitochondrial DNA (mtDNA) mutations in somatic mammalian cells, which is more than two orders of magnitude higher than the mutation frequency of nuclear DNA (nDNA), significantly correlates with development of a variety of mitochondrial diseases (neurodegenerative diseases, cardiomyopathies, type II diabetes mellitus, cancer, etc.). A direct cause—consequence relationship has been established between mtDNA mutations and aging phenotypes in mammals. However, the unclear nature of the high frequency of mtDNA mutations requires a comprehensive consideration of factors that contribute to this phenomenon: oxidative stress, features of structural organization and repair of the mitochondrial genome, ribonucleotide reductase activity, replication errors, mutations of nuclear genes encoding mitochondrial proteins.