线粒体DNA在心血管疾病中的研究进展

心血管系统能量消耗效率较高，因此，线粒体作是机体细胞唯一的供能细胞器，其在维持心血管系统正常病理生理功能中具有极其重要的作用。一旦线粒体功能受损，会导致一系列心血管疾病的发生。而线粒体DNA作为调控线粒体功能的主要遗传物质极可能与心血管疾病的发生发展密切相关。因此，现就线粒体DNA与心血疾病发生发展的研究进展做进一步综述。     

线粒体相关内质网膜:心血管疾病治疗的新靶点

线粒体相关内质网膜是指内质网和线粒体之间高度动态的紧密连接部分,参与维持内质网和线粒体的正常功能,与细胞脂质代谢、钙稳态、线粒体动力学、自噬和凋亡、内质网应激和炎症等密切相关。研究显示线粒体相关内质网膜功能异常或者数量和结构改变参与心血管疾病的发生发展。本文总结了线粒体相关内质网膜的功能,阐述了其在心血管疾病中的作用及可能机制,为线粒体相关内质网膜成为心血管疾病治疗的新靶点提供理论参考。     

内质网–线粒体交互在心血管疾病中的作用研究进展

线粒体和内质网的稳态在维持心血管正常功能中发挥重要作用,线粒体或内质网的结构功能异常参与了众多心血管疾病的发生发展。近年来研究发现线粒体与内质网存在物理和功能的交互,其交互作用调控线粒体、内质网功能,进而影响心肌细胞和平滑肌细胞的线粒体动力学平衡、钙转运及磷脂合成和转运。内质网–线粒体交互异常被认为是冠心病、心力衰竭、肺动脉高压和动脉粥样硬化等心血管疾病的关键机制。因此,理解内质网-线粒体交互机制可为预防和改善心血管疾病提供崭新靶点。     

血管内皮细胞线粒体动力学相关功能与心血管疾病关系的研究进展

细胞线粒体动力学相关功能是指线粒体通过不断地融合与分裂、线粒体自噬及线粒体-内质网结构偶联来维持细胞正常生理功能的过程。其异常与神经退行性病变、肿瘤、视神经萎缩及糖尿病等疾病的发生发展关系密切。近年来,血管内皮细胞（vascular endothelial cell,VEC）线粒体相关功能在心血管疾病中的研究受到广泛关注,研究发现VEC线粒体相关功能异常在心肌缺血/再灌注（I/R）损伤、冠状动脉粥样硬化、肺动脉高压及扩张型心肌病等疾病的发生发展中发挥重要作用。本文就VEC线粒体动力学相关功能及与心血管疾病的关系进行简要阐述。     

线粒体融合蛋白2在心血管疾病中的研究现状

线粒体是一个处于不断地融合与分裂过程中的动态细胞器。线粒体融合蛋白2(Mfn2)作为广泛分布于线粒体外膜和线粒体结合内质网膜上具有多重功能的蛋白,参与维持正常细胞功能。除了参与线粒体融合外,Mfn2还能够调节线粒体代谢、促进损伤线粒体的自噬、增强线粒体与内质网交流、维持内质网功能及通过调控线粒体外膜通透性和渗透性钙转运孔道的启闭参与细胞死亡过程等。另外,Mfn2基因还可通过调控Ras-Raf-ERK/MAPK和Ras-PI3K-Akt信号通路分别参与调控血管平滑肌细胞的增殖和凋亡过程。Mfn2的这一系列重要的生物学功能有助于其参与高血压、肺动脉高压、动脉粥样硬化、急性缺血/再灌损伤、扩张性心肌病、心肌肥大、心衰和肥胖糖尿病等多种心血管疾病的发生发展过程。研究Mfn2与心血管疾病的相关性也许能为临床提供一个心血管疾病潜在治疗的靶点。因此,本文将综述Mfn2在心血管疾病相关研究中的现状。     

心血管疾病线粒体蛋白质组学研究

线粒体是真核细胞重要的细胞器，线粒体功能障碍导致很多疾病包括心血管疾病。随着蛋白质组学技术的不断进步，从整体上研究不同病理状态下线粒体内蛋白质的含量变化渐受关注。本文综述线粒体蛋白质组学的主要技术方法进展及其在心血管疾病研究中的应用。     

线粒体及其蛋白质质量控制失调与动脉粥样硬化的关系

线粒体是哺乳动物细胞内重要的细胞器,作为细胞能量代谢和细胞死亡的调控中心,其功能异常会导致多种疾病的发生与发展。 线粒体功能依赖于线粒体蛋白质组的完整性和稳态,因此线粒体蛋白质质量控制系统对于维持线粒体稳态和机体健康十分重要。当线粒体及其蛋白质质量控制系统出现异常时,会直接损伤线粒体并出现异常线粒体蛋白堆积,发生细胞内环境紊乱,甚至细胞功能障碍,进而影响动脉粥样硬化性疾病的发生与发展。文章回顾了线粒体及其蛋白质质量控制系统在动脉粥样硬化性疾病发生发展中的作用,并对该领域未来的发展前景和挑战进行展望,以期为寻找与动脉粥样硬化性疾病密切相关的特异性线粒体蛋白提供线索。     

视神经萎缩1型线粒体融合蛋白在心血管疾病中的研究进展

心血管疾病严重威胁着人类健康,现已成为人类死亡的主要原因。能量代谢异常对心血管疾病的发生和发展起着关键作用,人体内90%的能量来源于线粒体,因此线粒体功能的稳定对于维持细胞正常形态与功能至关重要。既往研究发现,位于线粒体内膜上的视神经萎缩1型（OPA1）对线粒体功能的维持至关重要,越来越多的研究也表明,OPA1在动脉粥样硬化、心肌缺血再灌注损伤、心力衰竭、糖尿病心肌病等心血管疾病中发挥重要作用。本综述将概述有关OPA1蛋白功能,功能障碍以及与心血管疾病相关的临床表型,重点关注治疗OPA1突变引起的相关心血管疾病的当前治疗选择和未来前景。     

铜死亡发生机制及其在心血管疾病发生发展中的作用研究进展

铜作为一种微量元素,在细胞代谢和生物过程中均扮演着重要的角色。正常情况下,细胞中铜的浓度较低,而铜的过度积累会导致细胞死亡。铜死亡是近期发现的一种新型调节性细胞死亡,这种死亡不同于细胞凋亡、铁死亡及坏死等氧化应激诱导的细胞死亡,是一种与线粒体呼吸相关的铜依赖性细胞死亡模式。铜通过与三羧酸循环中的脂质酰化成分直接结合,导致脂质化蛋白质聚集,铁硫簇蛋白质丢失,从而引起蛋白质毒性应激,导致细胞死亡。充足的铜是维持心脏正常生理功能所必需的,机体内铜水平异常可能会引发一系列心血管疾病。目前,铜诱导的细胞死亡在动脉粥样硬化、糖尿病心肌病及心力衰竭等心血管疾病的发病机制中可见报道。然而,铜死亡在心血管疾病中的研究还处于初步阶段,进一步研究铜调控的细胞死亡通路在心血管疾病发生发展中的作用机制,可为心血管疾病的预防和治疗提供新的思路。     

线粒体介导心肌细胞凋亡的研究进展

心肌细胞凋亡对于机体而言具有双重作用机体可以消除发生突变的异常细胞或无功能的正常细胞;病理性的细胞凋亡可引起机体自身稳态平衡失调,导致各种心血管疾病.近年来,研究发现线粒体在心肌细胞凋亡过程中起着重要作用.本文就线粒体介导心肌细胞凋亡的分子生物学机制、线粒体介导心肌细胞凋亡与心血管疾病的关系及抗心肌细胞凋亡策略的研究作一综述.     

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...     

Mitochondrial adenine nucleotide transport and cardioprotection

Mitochondria are highly metabolically active cell organelles that not only act as the powerhouse of the cell by supplying energy through ATP production, but also play a destructive role by initiating cell death pathways. Growing evidence recognizes that mitochondrial dysfunction is one of the major causes of cardiovascular disease. Under de-energized conditions, slowing of adenine nucleotide transport in and out of the mitochondria significantly attenuates myocardial ischemia-reperfusion injury. The purpose of this review is to elaborate on and update the mechanistic pathways which may explain how altered adenine nucleotide transport can influence cardiovascular function. This article is part of a Special Issue entitled "Local Signaling in Myocytes".     

Mitochondrial proteomics—a tool for the study of metabolic disorders

Mitochondria are important for a number of life and death processes, such as energy production, creation of reactive oxygen species, and elicitation of stress responses. These responses range from induction of protein quality control and antioxidant systems to mitochondria elimination and cell death. Mitochondrial dysfunctions are involved in pathologies associated with many diseases, for example metabolic disorders, diabetes, cancers, cardiovascular and neurodegenerative diseases as well as obesity and aging. Mitochondrial proteomics can be a powerful tool in the study of these diseases, especially since it can cover mitochondrial proteins from several metabolic pathways, such as the citric acid cycle, fatty acid oxidation, and respiratory chain, as well as protein networks involved in stress responses. The mitochondrial proteome can consist of more than 1,000 different proteins. However, it is difficult to define the precise number, since mitochondria are dynamic and difficult to purify, and because an unknown number of proteins possess dual or multiple localization, depending on cell type and physiological conditions. This review describes several quantitative studies of proteins from mitochondria isolated by centrifugation, separated by various methods (e.g., electrophoresis and nanoLC), and analyzed by advanced mass spectrometry. We illustrate the methods by showing that multiple pathways and networks are affected in cells from patients carrying gene variations affecting a mitochondrial protein. The study of cultured skin fibroblasts from patients with ethylmalonic aciduria associated with variations in the genes coding for short-chain acyl-CoA dehydrogenase (SCAD) or ETHE1 are two of the examples. The possibility of obtaining mitochondrial proteomics data from whole cell proteomics studies is also exemplified by the involvement of liver mitochondria in metabolic syndrome.     

Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!

Mitochondrial health is critically dependent on the ability of mitochondria to undergo changes in mitochondrial morphology, a process which is regulated by mitochondrial shaping proteins. Mitochondria undergo fission to generate fragmented discrete organelles, a process which is mediated by the mitochondrial fission proteins (Drp1, hFIS1, Mff and MiD49/51), and is required for cell division, and to remove damaged mitochondria by mitophagy. Mitochondria undergo fusion to form elongated interconnected networks, a process which is orchestrated by the mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1), and which enables the replenishment of damaged mitochondrial DNA. In the adult heart, mitochondria are relatively static, are constrained in their movement, and are characteristically arranged into 3 distinct subpopulations based on their locality and function (subsarcolemmal, myofibrillar, and perinuclear). Although the mitochondria are arranged differently, emerging data supports a role for the mitochondrial shaping proteins in cardiac health and disease. Interestingly, in the adult heart, it appears that the pleiotropic effects of the mitochondrial fusion proteins, Mfn2 (endoplasmic reticulum-tethering, mitophagy) and OPA1 (cristae remodeling, regulation of apoptosis, and energy production) may play more important roles than their pro-fusion effects. In this review article, we provide an overview of the mitochondrial fusion and fission proteins in the adult heart, and highlight their roles as novel therapeutic targets for treating cardiac disease.     

Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system

Mitochondria are essential organelles that produce the cellular energy source, ATP. Dysfunctional mitochondria are involved in the pathophysiology of heart disease, which is associated with reduced levels of ATP and excessive production of reactive oxygen species. Mitochondria are dynamic organelles that change their morphology through fission and fusion in order to maintain their function. Fusion connects neighboring depolarized mitochondria and mixes their contents to maintain membrane potential. In contrast, fission segregates damaged mitochondria from intact ones, where the damaged part of mitochondria is subjected to mitophagy whereas the intact part to fusion. It is generally believed that mitochondrial fusion is beneficial for the heart, especially under stress conditions, because it consolidates the mitochondria's ability to supply energy. However, both excessive fusion and insufficient fission disrupt the mitochondrial quality control mechanism and potentiate cell death. In this review, we discuss the role of mitochondrial dynamics and mitophagy in the heart and the cardiomyocytes therein, with a focus on their roles in cardiovascular disease. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".     

Role of mitochondrial dysfunction in insulin resistance

Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. Thereby, when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications. In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue.     

Low-intensity exercise training delays heart failure and improves survival in female hypertensive heart failure rats

Exercise training improves functional capacity and quality of life in patients with heart failure. However, the long-term effects of exercise on mortality associated with hypertensive heart disease have not been well defined. In the present study, we investigated the effect of low-intensity exercise training on disease progression and survival in female spontaneously hypertensive heart failure rats. Animals with severe hypertension (16 months old) were treadmill trained (14.5 m/min, 45 min/d, 3 d/wk) until they developed terminal heart failure or were euthanized because of age-related complications. Exercise delayed mortality resulting from heart failure (P<0.001) and all causes (P<0.05) and transiently attenuated the systolic hypertension and contractile dysfunction observed in the sedentary animals but had no effect on cardiac morphology or contractile function in end-stage heart failure. Training had no effect on terminal myocardial protein expression of antioxidant enzymes, calcium handling proteins, or myosin heavy chain isoforms but was associated with higher cytochrome oxidase activity in cardiac mitochondria (P<0.05) and a greater mitochondrial content of cardiolipin, a phospholipid that is essential for optimal mitochondrial energy metabolism. In conclusion, low-intensity exercise training significantly delays the onset of heart failure and improves survival in female hypertensive heart failure rats without eliciting sustained improvements in blood pressure, cardiac function, or expression of several myocardial proteins associated with the cardiovascular benefits of exercise. The effects of exercise on cytochrome oxidase and cardiolipin provide novel evidence that training may improve prognosis in hypertensive heart disease by preserving mitochondrial energy metabolism.     

Free radicals, mitochondria, and oxidized lipids: the emerging role in signal transduction in vascular cells

Mitochondria have long been known to play a critical role in maintaining the bioenergetic status of cells under physiological conditions. It was also recognized early in mitochondrial research that the reduction of oxygen to generate the free radical superoxide occurs at various sites in the respiratory chain and was postulated that this could lead to mitochondrial dysfunction in a variety of disease states. Over recent years, this view has broadened substantially with the discovery that reactive oxygen, nitrogen, and lipid species can also modulate physiological cell function through a process known as redox cell signaling. These redox active second messengers are formed through regulated enzymatic pathways, including those in the mitochondrion, and result in the posttranslational modification of mitochondrial proteins and DNA. In some cases, the signaling pathways lead to cytotoxicity. Under physiological conditions, the same mediators at low concentrations activate the cytoprotective signaling pathways that increase cellular antioxidants. Thus, it is critical to understand the mechanisms by which these pathways are distinguished to develop strategies that will lead to the prevention of cardiovascular disease. In this review, we describe recent evidence that supports the hypothesis that mitochondria have an important role in cell signaling, and so contribute to both the adaptation to oxidative stress and the development of vascular diseases.     

心肌线粒体能量代谢在心血管疾病中的研究进展

目前心血管疾病已成为全球人类死亡的主要原因之一,线粒体作为三大营养物质经三羧酸循环产生ATP的主要场所,在心血管疾病的发生、进展过程中起着巨大影响作用。本文从心肌线粒体的能量代谢功能、相关调控途径、与心血管疾病的关系以及治疗药物方面入手,在心肌线粒体代谢方面为治疗心血管疾病提供思路与方向。     

Mitochondrial Cardiomyopathy: Pathophysiology,Diagnosis, and Management

Mitochondrial disease is a heterogeneous group of multisystemic diseases that develop consequent to mutations in nuclear or mitochondrial DNA. The prevalence of inherited mitochondrial disease has been estimated to be greater than 1 in 5,000 births; however, the diagnosis and treatment of this disease are not taught in most adult-cardiology curricula. Because mitochondrial diseases often occur as a syndrome with resultant multiorgan dysfunction, they might not immediately appear to be specific to the cardiovascular system. Mitochondrial cardiomyopathy can be described as a myocardial condition characterized by abnormal heart-muscle structure, function, or both, secondary to genetic defects involving the mitochondrial respiratory chain, in the absence of concomitant coronary artery disease, hypertension, valvular disease, or congenital heart disease. The typical cardiac manifestations of mitochondrial disease—hypertrophic and dilated cardiomyopathy, arrhythmias, left ventricular myocardial noncompaction, and heart failure—can worsen acutely during a metabolic crisis. The optimal management of mitochondrial disease necessitates the involvement of a multidisciplinary team, careful evaluations of patients, and the anticipation of iatrogenic and noniatrogenic complications.In this review, we describe the complex pathophysiology of mitochondrial disease and its clinical features. We focus on current practice in the diagnosis and treatment of patients with mitochondrial cardiomyopathy, including optimal therapeutic management and long-term monitoring. We hope that this information will serve as a guide for practicing cardiologists who treat patients thus affected.Key words: Cardiomyopathies/genetics/pathology/therapy, DNA, mitochondrial/analysis/genetics, energy metabolism/physiology, electron transport/physiology, genetic predisposition to disease, heart diseases/genetics, mitochondria/physiology, mitochondrial diseases/complications/diagnosis/genetics/physiopathology/drug therapy, risk factors, ventricular dysfunction, left/geneticsThe myocardium depends on a high level of aerobic metabolism to supply blood and energy substrate to all organs of the body. The mitochondria have a key role in energy production and in the growth and regulation of cardiac bioenergetic arrangements. Specific mitochondrial diseases have been attributed to mitochondrial mutations, and cardiac involvement is frequent. However, these syndromes are generally not covered comprehensively in cardiology curricula and might not be widely recognized by practicing cardiologists who treat adults. Recent research has shown that derangements of energy metabolism are ultimately implicated in most forms of heart failure. In this review, we describe the biologic characteristics of the mitochondria and their role in cardiac bioenergetic arrangements, discuss the spectrum of mitochondrial disease, and provide a guide for practicing cardiologists to use when treating patients affected by mitochondrial crisis.