线粒体动力学与2型糖尿病和糖尿病并发症关系的研究进展

线粒体动力学即线粒体融合和分裂保持动态平衡的过程,线粒体的融合与分裂过程决定线粒体形态的可塑性。这种动态平衡的稳定是维持线粒体功能和机体功能的前提和基础,并且受多种化学酶及蛋白等因素调节。因线粒体为细胞能量代谢中心,故线粒体动力学与人类代谢性疾病的关联日益受到重视。近年来,大量研究表明,线粒体动力学失衡可以引起胰岛素抵抗和β细胞功能障碍,并且与糖尿病并发症发生密切相关。     

线粒体融合与分裂:治疗缺血性心脏疾病的潜在靶点

线粒体是一种高度动态变化的细胞器,在细胞中不断融合与分裂,形成紧密连接的线粒体网络。这种融合与分裂的变化主要通过线粒体融合、分裂蛋白控制,并且越来越多的调控机制在逐渐被阐明。在线粒体融合、分裂蛋白的精确控制下,线粒体可在不断变化的生理环境中做出迅速准确的反应,这不仅对于线粒体的遗传以及维持其功能至关重要,还影响着细胞的生存状态。该变化过程与诸多生物学过程有着密切关系,如能量代谢、胚胎发育、自噬和凋亡等。近些年的研究发现,线粒体融合与分裂参与了缺血/再灌注损伤、心肌肥厚、心衰等过程。本文对线粒体融合与分裂的生物学过程进行阐述的同时,主要综述该过程与缺血性心脏疾病的研究进展及其潜在的治疗靶点。     

FoxO3a对线粒体功能的调控作用及机制

叉头框蛋白O3a(fork head box O3a, FoxO3a)是叉头框蛋白FOX转录因子O亚型家族中成员,作为一种转录调节因子在多种疾病的发生与发展中发挥重要调节作用。线粒体是细胞能量代谢的主要场所,也是维持细胞生长和功能的一类关键细胞器。线粒体功能受到多种转录因子调控。FoxO3a可定位于线粒体,通过调节细胞核与线粒体之间的相互作用,对线粒体功能产生重要影响,其机制与调节线粒体能量代谢、生物合成、自噬、分裂/融合,以及线粒体钙稳态密切相关。该文重点综述了FoxO3a的生物学功能、及其对线粒体的调控作用与机制。     

Bcl-2家族对线粒体质量控制的调控研究

线粒体质量控制是维持细胞生存及生存状态的重要机制,通过对线粒体形态、数量与质量的多维调控,维持细胞内稳态。研究发现Bcl-2家族与线粒体多种功能的调控密切相关,并参与调控线粒体自噬/细胞凋亡互调节及线粒体分裂、融合的动态变化,是线粒体质量控制的关键调控因子。该文主要综述Bcl-2家族对线粒体质量控制的影响及其主要调控机制。     

Bcl-2家族对线粒体质量控制的调控研究北大核心CSCD

线粒体质量控制是维持细胞生存及生存状态的重要机制,通过对线粒体形态、数量与质量的多维调控,维持细胞内稳态。研究发现Bcl-2家族与线粒体多种功能的调控密切相关,并参与调控线粒体自噬/细胞凋亡互调节及线粒体分裂、融合的动态变化,是线粒体质量控制的关键调控因子。该文主要综述Bcl-2家族对线粒体质量控制的影响及其主要调控机制。     

线粒体:急性肾损伤治疗的新靶标

线粒体是细胞的"能量工厂",是合成三磷酸腺苷的主要场所,为细胞的生命活动提供能量来源。正常肾单位依赖线粒体生成的ATP以维持对肾小球滤过液体的重吸收。线粒体对各种损伤性刺激敏感,线粒体功能障碍是急性肾损伤(AKI)的早期事件,在AKI的发生与进展中发挥重要作用,维持线粒体结构和功能的完整,有助于防治AKI的发生发展。在缺血再灌注大鼠肾脏组织中MPTP开放增加、ROS产生增加、ATP下降,而缺血后处理的肾组织MPTP开放减少、损伤较轻。应用线粒体靶向的多肽SS-31可抑制ROS产生、MPTP开放,对肾损伤起保护作用。免疫抑制剂环孢素A是一种m PTP的抑制剂,亦可抑制MPTP开放,从而发挥肾保护作用。线粒体形态学的改变也是缺血再灌注肾损伤的重要机制之一。将线粒体分裂主要的调控因子Drp1抑制可以显著抑制缺血再灌注诱导的线粒体分裂,并抑制小管细胞凋亡,减轻肾损伤。在体外培养的猪肾小管上皮细胞中,顺铂处理后出现激活线粒体信号通路包括开放MPTP、释放细胞色素c、活化胱天蛋白酶等,诱导细胞损伤。应用线粒体主要的抗氧化蛋白MnSOD的类似物MnTBAP可阻断顺铂诱导的线粒体活性氧产生以及细胞损伤。通过调控MnSOD信号可减少顺铂诱导的肾组织氧化应激以及凋亡。顺铂刺激亦可诱导肾小管上皮细胞自噬及线粒体自噬,促进线粒体自噬能够保护线粒体功能进而减轻顺铂诱导的肾小管上皮细胞损伤,抑制线粒体自噬损伤线粒体功能进一步加重顺铂诱导的肾小管上皮细胞损伤。随着对线粒体功能障碍在AKI发病机制的研究不断深入,多种靶向线粒体的药物被证实可通过调节线粒体的功能对抗肾脏损伤,这些药物包括线粒体分裂的抑制剂、MPTP孔抑制剂、线粒体抗氧化蛋白的类似物、线粒体靶向的醌类化合物以及多肽等,部分药物已经在临床试验中应用并验证,然而将其应用于临床急性肾损伤的防治仍需要更多以及更深入的工作。     

去氢骆驼蓬碱诱发PC12细胞凋亡时对线粒体融合分裂的影响

目的 探讨去氢骆驼蓬碱(HM)对PC12细胞线粒体功能损伤和线粒体融合分裂相关蛋白表达水平的影响。方法 PC12细胞分为细胞对照组、HM组、线粒体分裂抑制剂Mdivi-1组、HM+Mdivi-1组、线粒体裂变激动剂WY14643组、HM+WY14643组,药物浓度均为1、10、25、50、100μmol·L^-1,处理24 h,噻唑蓝(MTT)法检测细胞存活率,显微镜观察细胞形态;MitoTracker Red探针染色观察线粒体形态和纵横轴长度比值,JC-1染色检测线粒体膜电位,试剂盒检测ROS、ATP水平和乳酸脱氢酶(LDH)活性,免疫荧光染色法和Western blotting检测胱天蛋白酶3(caspase-3)、促凋亡蛋白(Bax)、细胞色素C(cyt-c)和线粒体融合蛋白(Mfn2)、线粒体分裂蛋白(Drp-1)的表达水平;电穿孔法转染Drp1的干扰序列,筛选转染效果好的siRNA序列,协同药物干预,通过荧光法、MTT法、免疫印迹法检测相关指标。结果 MTT结果显示,与细胞对照组比较,HM组、Mdivi-1组、HM+Mdivi-1组、WY14643组和HM...     

线粒体治疗在线粒体相关疾病治疗中的应用及展望

线粒体是哺乳动物细胞中供应能量、维持胞内稳态等多种功能的细胞器。目前已知有上百种疾病与线粒体功能缺陷有关。研究表明,外源线粒体可直接进入哺乳动物细胞,并可通过局部注射或静脉注射快速转移到动物或人体细胞内。线粒体治疗(mitotherapy)是通过将正常有功能的线粒体移植到具有线粒体缺陷的细胞中,从而对相关疾病进行防治的新策略。移植的线粒体在受体细胞内可发挥能量生成、维持自由基平衡、恢复细胞活力等功能。由于目前对线粒体相关疾病尚缺乏有效的治疗方法,线粒体治疗将为其防治提供一个新的途径。     

灯盏花乙素通过调节线粒体融合-分裂平衡抑制氧糖剥夺/复糖复氧诱导的N2a细胞焦亡

目的: 探讨灯盏花乙素对氧糖剥夺/复氧复糖(OGD/R)诱导的N2a细胞焦亡的影响及作用机制。方法: 建立N2a细胞OGD/R损伤模型,设立对照组、模型组、灯盏花乙素给药组和线粒体分裂抑制剂Mdivi-1组。通过CCK-8检测N2a细胞增殖能力,检测各组细胞培养基中LDH和IL-1β水平,通过JC-1探针检测线粒体膜电位,Western blot检测线粒体融合分裂关键蛋白(Drp-1、Mfn-1、Mfn-2、OPA-1)和细胞焦亡标志蛋白(Caspase-1、NLRP-3和GSDMD)表达。结果: 与对照组相比,OGD/R可显著降低N2a细胞活力,灯盏花乙素可明显提高N2a细胞活力。与模型组相比,灯盏花乙素可减少LDH的释放,降低Caspase-1和IL-1β水平,提高线粒体膜势能,降低Drp-1的表达水平,上调Mfn-1、Mfn-2和OPA-1的表达,并减少细胞焦亡关键蛋白NLRP-3和GSDMD的表达。进一步给予Drp-1抑制剂Mdivi-1,与模型组相比,Mdivi-1可明显提高线粒体膜势能,减少Caspase-1、NLRP-3和GSDMD的表达。结论: 灯盏花乙素可通过抑制线粒体过度分裂,改善线粒体融合-分裂失衡与功能异常,进而缓解OGD/R所致N2a细胞焦亡。     

线粒体在脓毒症肝损伤发病机制及治疗中的作用

线粒体功能障碍所致的细胞能量衰竭与脓毒症期间器官功能损害密切相关。肝脏细胞中存在丰富的线粒体,肝脏是脓毒症相关器官损伤的重要靶点。本文概述了线粒体在脓毒症肝损伤发病机制中的作用,以及线粒体修复过程的动态平衡对于维持线粒体稳态和减轻肝脏损伤的重要意义,以期为脓毒症治疗提供参考。     

Quercetin attenuates vascular calcification by inhibiting oxidative stress and mitochondrial fission

Vascular calcification is a strong independent predictor of increased cardiovascular morbidity and mortality and has a high prevalence among patients with chronic kidney disease. The present study investigated the effects of quercetin on vascular calcification caused by oxidative stress and abnormal mitochondrial dynamics both in vitro and in vivo. Calcifying vascular smooth muscle cells (VSMCs) treated with inorganic phosphate (Pi) exhibited mitochondrial dysfunction, as demonstrated by decreased mitochondrial potential and ATP production. Disruption of mitochondrial structural integrity was also observed in a rat model of adenine-induced aortic calcification. Increased production of reactive oxygen species, enhanced expression and phosphorylation of Drp1, and excessive mitochondrial fragmentation were also observed in Pi-treated VSMCs. These effects were accompanied by mitochondria-dependent apoptotic events, including release of cytochrome c from the mitochondria into the cytosol and subsequent activation of caspase-3. Quercetin was shown to block Pi-induced apoptosis and calcification of VSMCs by inhibiting oxidative stress and decreasing mitochondrial fission by inhibiting the expression and phosphorylation of Drp1. Quercetin also significantly ameliorated adenine-induced aortic calcification in rats. In summary, our findings suggest that quercetin attenuates calcification by reducing apoptosis of VSMCs by blocking oxidative stress and inhibiting mitochondrial fission.     

Drp1-dependent mitochondrial fission in cardiovascular disease

Mitochondria are highly dynamic organelles undergoing cycles of fusion and fission to modulate their morphology, distribution, and function, which are referred as ‘mitochondrial dynamics’. Dynamin-related protein 1 (Drp1) is known as the major pro-fission protein whose activity is tightly regulated to clear the damaged mitochondria via mitophagy, ensuring a strict control over the intricate process of cellular and organ dynamics in heart. Various posttranslational modifications (PTMs) of Drp1 have been identified including phosphorylation, SUMOylation, palmitoylation, ubiquitination, S-nitrosylation, and O-GlcNAcylation, which implicate a role in the regulation of mitochondrial dynamics. An intact mitochondrial homeostasis is critical for heart to fuel contractile function and cardiomyocyte metabolism, while defects in mitochondrial dynamics constitute an essential part of the pathophysiology underlying various cardiovascular diseases (CVDs). In this review, we summarize current knowledge on the critical role of Drp1 in the pathogenesis of CVDs including endothelial dysfunction, smooth muscle remodeling, cardiac hypertrophy, pulmonary arterial hypertension, myocardial ischemia–reperfusion, and myocardial infarction. We also highlight how the targeting of Drp1 could potentially contribute to CVDs treatments.     

Targeting protein interaction networks in mitochondrial dynamics for cancer therapy

Mitochondria are crucial organelles that provide energy via oxidative phosphorylation in eukaryotic cells and also have critical roles in growth, division, and the cell cycle, as well as the rapid adaptation required to meet the metabolic needs of the cell. Mitochondrial processes are highly dynamic; fusion and fission can vary with cell type, cellular context, and stress levels. Accumulating evidence demonstrates that an imbalance in mitochondrial dynamics leads to death in numerous types of human cancer cells. Therefore, modulating mitochondrial dynamics could be a therapeutic target. In this review, we provide an overview of the protein interaction networks involved in mitochondrial dynamics as effective and feasible drug targets and discuss the related potential therapeutic strategies for cancer.     

Mitochondrial dynamics as a therapeutic target for Alzheimer disease

Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer′s disease which likely plays a critical role in the pathogenesis of disease. Mitochondria are dynamic organelles and the balance of mitochondrial fission and fusion determines Our initial studies revealed an imbalance in mitochondrial fission and fusion in fibroblasts from sporadic AD patients compared with normal healthy fibroblasts from age-matched control patients. Later it was demonstrated that overexpression of familial Alzheimer disease(FAD)-causing AβPP mutant or exposure to soluble Aβ oligomers led to mitochondrial fragmentation and redistribution in neuronal cells along with altered expression of mitochondrial fission/fusion proteins. Marked mitochondrial fragmentation and abnormal mitochondrial distribution in the pyramidal neurons along with mitochondrial dysfunction in the brain of AD mouse model CRND8 as early as three months of age before the accumulation of amyloid pathology. Importantly,we demonstrate significant changes in the expression and distribution of mitochondrial fission and fusion proteins in vivo in AD in consistent with a shifted mitochondrial dynamics towards excessive fission. Most recently,we demonstrated that genetic and pharmaceutical methods to rescue mitochondrial morphology and distribution could effectively restore Aβ-induced mitochondrial function and alleviate synaptic dysfunction both in vitro and in vivo,suggesting a causal involvement of mitochondrial dynamics in mediating Aβ-induced mitochondrial dysfunction. Taken together,we suggest that such a fundamental shift in mitochondrial dynamics negatively impacts all aspect of mitochondrial function such as impaired bioenergetics,increased structural damage and ROS production and loss of mt DNA integrity which causes synaptic dysfunction and neuronal dysfunction that is critical to AD pathogenesis. Therefore,strategies to modify abnormal mitochondrial dynamics may be an attractive therapeutic intervention target for AD.     

The mitochondrial dynamics of Alzheimer's disease and Parkinson's disease offer important opportunities for therapeutic intervention

Mitochondrial dynamics play a crucial role in the pathobiology underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Although a complete scientific understanding of these devastating conditions has yet to be realized, alterations in mitochondrial fission and fusion, and in the protein complexes that orchestrate mitochondrial fission and fusion, have been well established in AD- and PD-related neurodegeneration. Whether fission/fusion disruption in the brain is a causal agent in neuronal demise or a product of some other upstream disturbance is still a matter of debate; however, in both AD and PD, the potential for successful therapeutic amelioration of degeneration via mitochondrial protection is high. We here discuss the role of mitochondrial dynamics in AD and PD and assess the need for their therapeutic exploitation.     

Mitochondrial dynamics proteins as emerging drug targets

The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure–function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.     

Schaftoside ameliorates oxygen glucose deprivation-induced inflammation associated with the TLR4/Myd88/Drp1-related mitochondrial fission in BV2 microglia cells

Background

Neuroinflammation plays a major role in the development of ischemic stroke, and regulation of the proinflammatory TLR4 signaling pathway in microglia stands to be a promising therapeutic strategy for stroke intervention. Recently, the homeostasis of mitochondrial dynamics has also been raised as a vital component in maintaining neuronal health, but its relevance in microglia hasn't been investigated. Schaftoside, a natural flavonoid compound and a promising treatment for inflammation, has demonstrated potency against LPS-induced lung inflammation in mice; however, its action on TLR4-induced neuroinflammation and mitochondrial dynamics in microglia is still unknown.

Fructose-palmitate based high calorie induce steatosis in HepG2 cells via mitochondrial dysfunction: An in vitro approach

A proper in vitro model for conducting research on high energy food induced steatosis via defective energy metabolism in the liver is not visible in the literature. The present study developed an in vitro model in HepG2 cell line to mimic high energy diet induced steatosis in liver via mitochondrial dysfunction. For this, HepG2 cells were treated with fructose (100 mM) and palmitate (100 μM) for about 24 h and subjected for biochemical analysis relevant to lipogenesis and mitochondrial biology. Our findings showed that fructose-palmitate treatment caused significant lipid accumulation and rise in lipogenic proteins. Further studies showed alteration in mitochondrial integrity, dynamics and oxidative phosphorylation. Mitochondrial integrity was affected by the dissipation of trans-membrane potential, surplus mitochondrial superoxide with calcium overload. Similarly, mitochondrial dynamics were altered with up regulation of mitochondrial fission proteins: DRP1 and FIS1, cytochrome c release, caspase-3 activity and apoptosis. Various components of the electron transport chain: complex I, II, III and IV were altered with significant depletion in oxygen consumption. Overall our findings illustrate the dominant role of mitochondria in the genesis of high fructose-palmitate induced steatosis in HepG2 cells. Since continuous high energy food consumption is the main inducer of steatosis, this model is found to be an ideal one for preliminary and basic research in the area of liver disease via mitochondrial dysfunction.     

Dynamin-related protein-1 as potential therapeutic target in various diseases

Mitochondria can interchange morphology due to their dynamic nature. It can exist in either fragmented disconnected arrangement or elongated interconnected mitochondrial networks due to fission and fusion, respectively. The recent studies have revealed the remarkable and unexpected insights into the physiological impact and molecular regulation of mitochondrial morphology. The balance between fission and fusion governs the faith of the cell. The active targeting of DRP 1 to the outer mitochondrial membrane (OMM) is done by non-GTPase receptor proteins such as mitochondrial fission factor, mitochondrial fission protein 1 and mitochondrial elongation factor 1. The active targeting of DRP 1 to OMM leads to the fission of mitochondria. However, the imbalance of DRP 1-dependent mitochondrial fission and modulation of equilibrium of fission and fusion has been documented to be involved in several cardiovascular and neurodegenerative disorders. In this review, we are focusing on the active participation of DRP 1 in various diseases and also the factors responsible for the activation of DRP 1 for its action.