线粒体质量控制与心血管疾病

心肌线粒体是心脏能量代谢的主要部位,其功能障碍可导致多种心血管疾病.线粒体质量控制主要通过调控线粒体的生物发生、融合、分裂和自噬,以保证线粒体形态、数量和质量的相对稳定,以维持其结构和功能的完整性.线粒体的质量控制体系在缺血性心脏病、糖尿病性心肌病、心力衰竭、动脉粥样硬化和高血压中发挥重要作用.     

线粒体动力学、线粒体自噬和心血管疾病

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、凋亡和线粒体自噬的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,并有效地抑制功能障碍线粒体的积累。由于心脏作为一个复杂而高耗能的器官,心肌细胞严重地依赖线粒体氧化代谢过程作为其能量和营养供应的来源。许多研究表明,线粒体融合、分裂和线粒体自噬的诸多影响和调控功能的因子都与各种心血管疾病有关,维持线粒体的功能和其完整性对正常心肌细胞的运行是至关重要的。在这篇的综述中,我们将重点概述一下线粒体的融合、分裂和线粒体自噬的诸多调控因子与心血管疾病的最新研究进展。     

TFAM在卵母细胞成熟和早期胚胎发育中的作用

<正>线粒体在生殖细胞的发育和功能发挥着重要的作用。线粒体含有一组母系遗传基因,在生殖细胞发育过程中应将未受活性氧损伤的线粒体遗传给后代。核基因编码的线粒体转录因子A(TFAM)是线粒体转录和翻译的重要调控因子,调控线粒体DNA的拷贝,影响卵母细胞和胚胎的发育。本文主要从TFAM对卵母细胞、胚胎影响的角度进行了综述。1 TFAM的生物学特性线粒体基因与其产物在卵母细胞的形成和发育中扮演着     

线粒体与心肌细胞凋亡的研究进展

心肌细胞凋亡 (ａｐｏｐｔｏｓｉｓ)是心肌细胞的一种程序性死亡 ,它在心脏的发育及心力衰竭、原发性高血压、心律失常等许多心脏疾病的病理生理中起着重要作用。线粒体是细胞产生能量的细胞器 ,维持机体生命活动所需的能量 ,90 %以上都是由它以三磷酸腺苷 (ＡＴＰ)形式产生。现在的研究证实 ,线粒体在介导细胞凋亡中起着重要作用。在心肌细胞中 ,线粒体约占心肌细胞总体积的 4 5 %。研究发现 ,在心肌细胞凋亡时 ,线粒体结构与功能发生明显改变 ,且与心肌细胞凋亡显著相关[1 3] 。本文主要综述线粒体在心肌细胞凋亡中的作用及其意义。一、…     

线粒体功能障碍与血管内皮损伤的研究进展

线粒体功能障碍会导致ATP的生成减少,活性氧的产生增加,被认为是血管内皮损伤的触发因素之一。许多因素与线粒体功能障碍有关,如线粒体DNA突变、线粒体融合与分裂失衡、线粒体自噬受损等。本文综述了线粒体的质量控制过程和线粒体功能障碍在血管内皮损伤中的作用机制,以期为动脉粥样硬化的有效防治提供新的思路。     

线粒体质量控制在肾脏缺血再灌注损伤中作用机制的研究进展

肾脏缺血再灌注损伤(IRI)的发病机制复杂且缺乏有效的治疗手段.线粒体质量控制失调在肾脏IRI的发生发展中具有重要作用,其中线粒体生物合成、线粒体动力学及线粒体自噬对肾小管细胞的线粒体质量控制极为关键.以线粒体质量控制为靶点,可为肾脏IRI提供潜在的治疗策略.     

线粒体质量控制在2型糖尿病发生发展及治疗中的作用研究进展

线粒体作为细胞能量代谢的核心参与者，参与了胰岛素抵抗和2型糖尿病发生机制。线粒体质量控制系统包括线粒体生物合成、线粒体动力学、线粒体自噬。线粒体质量控制通过不断融合/分裂改变其形状及大小、生物合成新生线粒体补充线粒体池和自噬将包裹受损的线粒体传递至溶酶体进行清除，维持相对稳定的线粒体数量和质量的动态过程，是保证线粒体健康和维持线粒体稳态的重要机制。糖尿病患者在线粒体自噬、动力学和生物合成方面存在缺陷，即线粒体质量控制失调，导致线粒体功能障碍，诱发β细胞功能紊乱甚至死亡。深入了解线粒体质量控制与T2DM的关系，通过调节线粒体生物合成、线粒体融合/分裂和线粒体自噬等相关因子表达，影响线粒体质量控制，从而改善外周组织的胰岛素敏感性、提高葡萄糖刺激胰岛素分泌能力、促进白色脂肪褐变和减少脂肪异位沉积，达到降糖、降脂、治疗T2DM的目的。     

基于中医阴阳理论探讨线粒体与抑郁症的相关性

线粒体是细胞能量代谢的中心,线粒体能量代谢障碍是抑郁症发生发展的重要病理机制,通过线粒体质量控制体系可以维持或调节线粒体的功能。在抑郁症的发病过程中,慢性应激会导致人体生理功能稳态失衡,通过多种病理途径导致线粒体形态和功能受损。而在线粒体质量调控机制中蕴含着中医的阴阳互根互用、对立制约、消长平衡等内容。因此,以中医阴阳理论为基础,以细胞生物分子机制为对象,围绕线粒体质量控制体系阐述线粒体能量代谢调控的微观机制,探讨其与抑郁症的相关性,不仅可以深入理解抑郁症发病机制,而且还能够结合中医的特色理论优势,为指导临床中西医结合治疗抑郁症的方式方法以及相关药物的研发提供了思路。     

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。     

线粒体质量控制在脓毒症急性肺损伤中的作用

脓毒症诱导的急性肺损伤（ALI）临床常见,发病率和死亡率高。线粒体质量控制在脓毒症ALI中发挥着至关重要的作用,其过程包括线粒体生物合成、线粒体融合与分裂和线粒体自噬等。线粒体质量控制失调会引起线粒体功能障碍,从而诱发肺内皮细胞程序性死亡,是ALI发生的重要机制。因此,当前很多研究关注线粒体质量控制的作用,并将其作为脓毒症ALI的靶向治疗策略。本文就线粒体质量控制在脓毒症ALI的相关研究进展展开综述,为临床防治脓毒症ALI提供理论参考依据。     

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。     

Metabolic and functional consequences of chronic alcoholism on the rat heart

Conflicting data concerning cardiac function and energy metabolism in chronic alcoholism have been reported. Previous studies have shown preferential metabolism of ketone bodies and acetate, a primary metabolite of ethanol, leading to diminished myocardial high energy phosphate stores. We evaluated the following parameters in chronically, severely alcoholic rats: cardiac function utilizing working heart preparations with variable afterload; high energy phosphate stores; and mitochondrial respiratory activity. At low work load no differences existed in hemodynamic measurements between hearts from alcoholic and control animals; however, immediately after the imposition of an increased afterload, hearts from alcoholic animals exhibited a subnormal increment in pressure development. This decrement normalized during the following 30 min of perfusion. ATP and creatinine phosphate levels in hearts from alcoholic animals which were excised and immediately frozen and in those which had been perfused as working heart preparations for 120 min were not different from those found in controls. Studies on mitochondrial respiration revealed a diminished activity of the myocardium from alcoholic rats to utilize glutamate as a substrate; however, the utilization of other substrates was unaffected by alcohol consumption. It is concluded that in chronically alcoholic rats minor changes occur in cardiac function; the heart maintains normal high energy stores; however, alternative substrates are utilized for the production of energy.     

Mouse models of mitochondrial dysfunction and heart failure

Mitochondria in the adult mammalian heart have a tremendous capacity for oxidative metabolism, and the conversion of energy by these pathways is critical for proper cardiac function. This review describes mouse models relating mitochondrial metabolism to cardiac function through gain- or loss-of-function approaches that manipulate mitochondrial energy transduction or ATP synthetic pathways. Mouse models of mitochondrial defects are relevant to genetic and acquired forms of human cardiomyopathy. Examples include inborn errors in mitochondrial metabolism or end-stage heart failure. Conversely, chronic reliance on energy production via mitochondrial fatty acid oxidation, such as occurs in the diabetic heart, likely leads to maladaptive sequelae including cellular lipotoxicity and mitochondrial dysfunction. Collectively, these model systems have allowed us to begin to dissect the relationship between mitochondrial metabolism and the development of cardiomyopathy and to define the molecular pathways regulating cardiac mitochondrial number and function.     

RSA 2004: combined basic research satellite symposium - session three: alcohol and mitochondrial metabolism: at the crossroads of life and death

This article summarizes the proceedings of the RSA 2004 Combined Basic Research Satellite Meeting convened at the Westin Bayshore Resort and Marina, Vancouver, CA. One of the sessions "Alcohol and mitochondrial metabolism: At the crossroads of life and death" featured five speakers and was chaired by Drs. Jan Hoek and Sam Zakhari. The presentations were 1) Introduction: Alcohol and cellular energy metabolism by Jan Hoek, 2) Ethanol-dependent dysfunction of mitochondrial energy metabolism: the role of NO by Victor Darley-Usmar, 3) Ethanol and apoptosis in the heart by Gyorgy Hajnoczky, 4) Alcohol and mitochondrial biogenesis in development by Thomas Knudsen, and 5) Alcohol, mitochondrial function and cardiac preconditioning by Daria Mochly-Rosen.     

Heart spotting

Cardiac function depends upon several factors, including adequate cellular mass, intact contractile machinery, and adequate production of ATP. An appropriate homeostasis on all these levels is crucial for the daunting life-long task the myocardium faces. Not surprisingly, many alterations in the above factors have been spotted when the heart fails and hypothesized to play a causal role in the genesis of the failing heart. Indeed, development of cardiac hypertrophy and failure is associated with chamber remodeling as well as with changes of the phenotype at the level of the individual myocyte. Disturbed energy metabolism with impaired fatty acid oxidation and lower expression of proteins involved in ATP synthesis occurs during myocardial hypertrophy and heart failure. The altered expression of proteins from metabolic pathways may reflect mitochondrial dysfunction as a feature of the transition from compensated myocardial hypertrophy with preserved fatty acid metabolism to impaired energy metabolism in heart failure.     

Metabolic fingerprint of ischaemic cardioprotection: importance of the malate-aspartate shuttle

The convergence of cardioprotective intracellular signalling pathways to modulate mitochondrial function as an end-target of cytoprotective stimuli is well described. However, our understanding of whether the complementary changes in mitochondrial energy metabolism are secondary responses or inherent mechanisms of ischaemic cardioprotection remains incomplete. In the heart, the malate-aspartate shuttle (MAS) constitutes the primary metabolic pathway for transfer of reducing equivalents from the cytosol into the mitochondria for oxidation. The flux of MAS is tightly linked to the flux of the tricarboxylic acid cycle and the electron transport chain, partly by the amino acid l-glutamate. In addition, emerging evidence suggests the MAS is an important regulator of cytosolic and mitochondrial calcium homeostasis. In the isolated rat heart, inhibition of MAS during ischaemia and early reperfusion by the aminotransferase inhibitor aminooxyacetate induces infarct limitation, improves haemodynamic responses, and modulates glucose metabolism, analogous to effects observed in classical ischaemic preconditioning. On the basis of these findings, the mechanisms through which MAS preserves mitochondrial function and cell survival are reviewed. We conclude that the available evidence is supportive of a down-regulation of mitochondrial respiration during lethal ischaemia with a gradual 'wake-up' during reperfusion as a pivotal feature of ischaemic cardioprotection. Finally, comments on modulating myocardial energy metabolism by the cardioprotective amino acids glutamate and glutamine are given.     

Morphological dynamics of mitochondria — A special emphasis on cardiac muscle cells

Mitochondria play a critical role in cellular energy metabolism, Ca²⁺ homeostasis, reactive oxygen species generation, apoptosis, aging, and development. Many recent publications have shown that a continuous balance of fusion and fission of these organelles is important in maintaining their proper function. Therefore, there is a steep correlation between the form and function of mitochondria. Many major proteins involved in mitochondrial fusion and fission have been identified in different cell types, including heart. However, the functional role of mitochondrial dynamics in the heart remains, for the most part, unexplored. In this review we will cover the recent field of mitochondrial dynamics and its physiological and pathological implications, with a particular emphasis on the experimental and theoretical basis of mitochondrial dynamics in the heart.     

Developmental changes in energy substrate use by the heart.

Marked changes in intermediary metabolism occur during development of the heart. In the fetus, the heart utilises lactate and glucose as its main energy substrates, while in the adult, fatty acids are the main energy substrate. The transition from carbohydrate to fatty acid metabolism is a complex process which involves maturation of mitochondrial processes and dramatic changes in circulating levels of fatty acids and lactate. In addition, developmental changes in the use of energy substrates also involve changes in the regulation of the enzymes involved in both carbohydrate and fatty acid utilisation. This paper reviews these changes in intermediary metabolism which occur during myocardial development. The metabolic differences that exist between immature and adult hearts may explain the observed differences in the ability of immature hearts to withstand hypoxaemia or ischaemia.     

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 dynamics in heart failure

Mitochondria have been widely studied for their critical role in cellular metabolism, energy production, and cell death. New developments in research on mitochondria derived from studies in yeast have led to the discovery of entirely new mitochondrial processes that have implications for mitochondrial function in heart failure. Recent studies have identified that maintaining normal mitochondrial morphology and function depends on the dynamic balance of mitochondrial fusion and fission (division). Mitochondrial fusion and fission are constant ongoing processes, which are essential for the maintenance of normal mitochondrial function. Studies in heart failure have been limited but suggest a possible reduction in mitochondrial fusion. As mitochondrial fusion and fission have important links to apoptosis, a key mechanism of loss of cardiac myocytes in heart failure, there are many implications for both heart failure research and treatment.