mitochondrial fusion

线粒体融合
  • 文章类型: Journal Article
    线粒体完整性和功能构成细胞功能和修复过程的先决条件。我们先前已经表明,不同细胞类型的线粒体在低温条件下表现出明显的碎片化。这个裂变,伴随着细胞ATP含量的下降,在37°C时显示出可逆性。然而,目前尚不清楚目前讨论的其他器官修复温度是否允许线粒体重建。因此,我们在培养的猪主动脉内皮细胞模型中研究不同复温温度对线粒体再融合和功能的影响.在4℃下用葡萄糖(5mM)和去铁胺(1mM)在Krebs-Henseleit缓冲液中将内皮细胞冷孵育48小时后,观察到明显的线粒体裂变。在细胞培养基中复温2小时后,在重新加温后,仍存在明显的裂变,温度为10°C或15°C。在21°C时,一些重新融合是可见的,在25°C时变得更加明显。与对照细胞相似的管状线粒体网络仅在37°C时重新出现。ATP含量在4°C时从3.6±0.4降低到1.6±0.4nmol/106个细胞,并且在将细胞重新加温到10°C和15°C时进一步降低。在21°C复温后的值与复温前的值相似,而ATP在较高的复温温度下逐渐增加。代谢活性下降到5±11%的对照值在4℃的培养过程中,并随着温度的升高而恢复到36±10%在25℃和78±17%在37℃。单层的完整性,在4°C时受到很大程度的干扰(内皮细胞之间的间隙大;细胞损伤≤1%),显示从15°C向上的部分恢复,在37°C时完全恢复。25°C时的内皮修复过程(划痕分析)明显低于37°C时的过程。这些数据表明,对于线粒体完整性和功能的重建,低于21°C的修复温度不是最佳的。为了这个目标,至少需要25°C的温度,30°C更优,37°C产生最佳结果。
    Mitochondrial integrity and function constitute a prerequisite for cellular function and repair processes. We have previously shown that mitochondria of different cell types exhibit pronounced fragmentation under hypothermic conditions. This fission, accompanied by a decline of cellular ATP content, showed reversibility at 37◦C. However, it is unclear whether other temperatures as currently discussed for reconditioning of organs allow this reconstitution of mitochondria. Therefore, we here study in a model of cultured porcine aortic endothelial cells how different rewarming temperatures affect mitochondrial re-fusion and function. After 48 h cold incubation of endothelial cells in Krebs-Henseleit buffer with glucose (5 mM) and deferoxamine (1 mM) at 4◦C pronounced mitochondrial fission was observed. Following 2 h rewarming in cell culture medium, marked fission was still present after rewarming at 10◦ or 15◦C. At 21◦C some re-fusion was visible, which became more marked at 25◦C. Networks of tubular mitochondria similar to control cells only re-appeared at 37◦C. ATP content decreased at 4◦C from 3.6 ± 0.4 to 1.6 ± 0.4 nmol/106 cells and decreased even further when rewarming cells to 10◦ and 15◦C. Values after rewarming at 21◦C were similar to the values before rewarming while ATP gradually increased at higher rewarming temperatures. Metabolic activity dropped to 5 ± 11% of control values during 4◦C incubation and recovered with increasing temperatures to 36 ± 10% at 25◦C and 78 ± 17% at 37◦C. Integrity of monolayers, largely disturbed at 4◦C (large gaps between endothelial cells; cell injury ≤ 1%), showed partial recovery from 15◦C upwards, complete recovery at 37◦C. Endothelial repair processes (scratch assay) at 25◦C were clearly inferior to those at 37◦C. These data suggest that reconditioning temperatures below 21◦C are not optimal with regard to reconstitution of mitochondrial integrity and function. For this goal, temperatures of at least 25◦C appear required, with 30◦C being superior and 37◦C yielding the best results.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    生长软骨细胞分化进程之间的机制关系,基质矿化,氧化代谢,在ATDC5鼠软骨祖细胞细胞系中检查了线粒体的含量和结构。软骨细胞分化的进展与氧化磷酸化的显著增加(p≤0.05)~2倍相关。然而,随着基质矿化的进展,氧化代谢下降。在没有矿化的情况下,软骨细胞外基质mRNA表达Col2a1,Aggrecan,和Col10a1在统计学上(p≤0.05)比矿化培养物中观察到的高2-3倍。相比之下,与促进基质矿化相关的BSP和Phex在统计学上(p≤0.05)显示出较高的〜2-4表达,而FGF23磷酸盐调节因子在矿化培养物中显著较低(~50%)。在非矿化和矿化培养基条件下诱导分化的培养物显示出统计学上更高的基础氧化代谢和ATP产生。与矿化的培养物相比,分化的非矿化培养物中的最大呼吸和备用氧化能力显着提高(p≤0.05)。氧化代谢增加与每个细胞的线粒体体积增加和线粒体融合有关,而矿化减少了线粒体体积,似乎与裂变有关。未分化和矿化的细胞显示与肌动蛋白细胞骨架的线粒体共定位增加。检测与线粒体分裂、凋亡和线粒体自噬相关的蛋白质,分别,在矿化培养物中,免疫表达水平与裂变和凋亡的增加一致。这些结果表明,软骨细胞分化与细胞内结构重组有关,促进线粒体含量增加和融合,从而增加氧化代谢。矿化,然而,不需要来自氧化代谢的能量;相反,在矿化过程中,线粒体似乎经历裂变和线粒体自噬。总之,这些研究表明,当软骨细胞经历肥大分化时,它们增加了氧化代谢,但是随着矿化的进行,新陈代谢下降。线粒体结构也经历了结构重组,这进一步支持了软骨细胞分化过程中的氧化能力。因此,线粒体首先进行融合以支持氧化代谢增加,然后在矿化过程中发生裂变,促进他们的程序化死亡。
    The mechanistic relationships between the progression of growth chondrocyte differentiation, matrix mineralization, oxidative metabolism, and mitochondria content and structure were examined in the ATDC5 murine chondroprogenitor cell line. The progression of chondrocyte differentiation was associated with a statistically significant (p ≤ 0.05) ~2-fold increase in oxidative phosphorylation. However, as matrix mineralization progressed, oxidative metabolism decreased. In the absence of mineralization, cartilage extracellular matrix mRNA expression for Col2a1, Aggrecan, and Col10a1 were statistically (p ≤ 0.05) ~2-3-fold greater than observed in mineralizing cultures. In contrast, BSP and Phex that are associated with promoting matrix mineralization showed statistically (p ≤ 0.05) higher ~2-4 expression, while FGF23 phosphate regulatory factor was significantly lower (~50%) in mineralizing cultures. Cultures induced to differentiate under both nonmineralizing and mineralizing media conditions showed statistically greater basal oxidative metabolism and ATP production. Maximal respiration and spare oxidative capacity were significantly elevated (p ≤ 0.05) in differentiated nonmineralizing cultures compared to those that mineralized. Increased oxidative metabolism was associated with both an increase in mitochondria volume per cell and mitochondria fusion, while mineralization diminished mitochondrial volume and appeared to be associated with fission. Undifferentiated and mineralized cells showed increased mitochondrial co-localization with the actin cytoskeletal. Examination of proteins associated with mitochondria fission and apoptosis and mitophagy, respectively, showed levels of immunological expression consistent with the increasing fission and apoptosis in mineralizing cultures. These results suggest that chondrocyte differentiation is associated with intracellular structural reorganization, promoting increased mitochondria content and fusion that enables increased oxidative metabolism. Mineralization, however, does not need energy derived from oxidative metabolism; rather, during mineralization, mitochondria appear to undergo fission and mitophagy. In summary, these studies show that as chondrocytes underwent hypertrophic differentiation, they increased oxidative metabolism, but as mineralization proceeds, metabolism decreased. Mitochondria structure also underwent a structural reorganization that was further supportive of their oxidative capacity as the chondrocytes progressed through their differentiation. Thus, the mitochondria first underwent fusion to support increased oxidative metabolism, then underwent fission during mineralization, facilitating their programed death.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    铁凋亡是一种铁依赖性细胞死亡形式,可引发肿瘤中的脂质过氧化(LPO)。近年来,人们对铁中毒的兴趣越来越大,但是如何推动它向前转化医学仍处于迷雾之中。尽管实验性的铁凋亡诱导剂如RSL3和erastin已经在体外证明了生物活性,动物模型中不良的抗肿瘤结果限制了它们的发展。在这项研究中,我们揭示了一种新的铁死亡诱导物,奥沙利铂-青蒿琥酯(OART),在体外和体内表现出相当大的生物活性,我们验证了其在癌症免疫疗法中的可行性。对于机制,OART诱导细胞质和线粒体LPO促进肿瘤铁性凋亡,通过抑制谷胱甘肽介导的铁凋亡防御系统,增强铁依赖的Fenton反应,启动线粒体LPO。被破坏的线粒体膜电位,受干扰的线粒体融合和裂变,以及二氢乳清酸脱氢酶的下调共同促进线粒体LPO。因此,OART通过释放损伤相关分子模式和促进抗原呈递细胞成熟来增强肿瘤的免疫原性,从而将肿瘤环境从免疫抑制转变为免疫敏感。通过建立体内肿瘤发生和肺转移模型,我们验证了OART改善了系统免疫反应.总之,OART在转化医学中基于铁凋亡的癌症治疗具有巨大的临床潜力。
    Ferroptosis is an iron-dependent cell death form that initiates lipid peroxidation (LPO) in tumors. In recent years, there has been growing interest on ferroptosis, but how to propel it forward translational medicine remains in mist. Although experimental ferroptosis inducers such as RSL3 and erastin have demonstrated bioactivity in vitro, the poor antitumor outcome in animal model limits their development. In this study, we reveal a novel ferroptosis inducer, oxaliplatin-artesunate (OART), which exhibits substantial bioactivity in vitro and vivo, and we verify its feasibility in cancer immunotherapy. For mechanism, OART induces cytoplasmic and mitochondrial LPO to promote tumor ferroptosis, via inhibiting glutathione-mediated ferroptosis defense system, enhancing iron-dependent Fenton reaction, and initiating mitochondrial LPO. The destroyed mitochondrial membrane potential, disturbed mitochondrial fusion and fission, as well as downregulation of dihydroorotate dehydrogenase mutually contribute to mitochondrial LPO. Consequently, OART enhances tumor immunogenicity by releasing damage associated molecular patterns and promoting antigen presenting cells maturation, thereby transforming tumor environment from immunosuppressive to immunosensitive. By establishing in vivo model of tumorigenesis and lung metastasis, we verified that OART improves the systematic immune response. In summary, OART has enormous clinical potential for ferroptosis-based cancer therapy in translational medicine.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Preprint
    线粒体功能障碍与特发性和家族性帕金森病(PD)有关。我们先前已将RCC1样(RCC1L)鉴定为对线粒体融合重要的线粒体内膜蛋白。在这里,为了测试RCC1L线粒体功能的缺陷是否可能与PD病理有关,我们已经选择性地消融了小鼠多巴胺能(DA)神经元中的Rcc1l基因。导致PD样表型,包括进行性运动异常,伴有黑质纹状体的进行性退化。实验组和对照组在2、3-4和5-6月龄进行检查。在野外任务中测试动物以量化焦虑,探索性驱动,运动,和不动;并在气缸测试中量化饲养行为。从3-4个月开始,雌性和雄性Rcc1l敲除小鼠均表现出僵硬的肌肉和静息性震颤,与杂合或野生型同窝对照相比,后凸畸形和生长缺陷。Rcc1l敲除小鼠在3-4个月时开始显示运动损伤,进展到5-6个月大,Rcc1l敲除小鼠死亡的年龄。进行性运动障碍与黑质致密部(SNc)中酪氨酸羟化酶免疫反应性的进行性和显着降低有关,纹状体中黑色DA投影的急剧损失。早在1.5-2.5个月大的Rcc1l敲除小鼠的SNc神经元中,营养不良的球形线粒体就很明显,直到5-6个月,逐渐变得更加明显。一起,结果表明,RCC1L蛋白对DA神经元的体内线粒体功能至关重要。该小鼠模型的进一步表征将确定它是否代表用于PD体内研究的新模型。以及人类RCC1L基因作为可能增加人类PD发生和严重程度的危险因素的假定作用。
    Mitochondrial dysfunction has been linked to both idiopathic and familial forms of Parkinson\'s disease (PD). We have previously identified RCC1-like (RCC1L) as a protein of the inner mitochondrial membrane important to mitochondrial fusion. Herein, to test whether deficits in RCC1L mitochondrial function might be involved in PD pathology, we have selectively ablated the Rcc1l gene in the dopaminergic (DA) neurons of mice. A PD-like phenotype resulted that includes progressive movement abnormalities, paralleled by progressive degeneration of the nigrostriatal tract. Experimental and control groups were examined at 2, 3-4, and 5-6 months of age. Animals were tested in the open field task to quantify anxiety, exploratory drive, locomotion, and immobility; and in the cylinder test to quantify rearing behavior. Beginning at 3-4 months, both female and male Rcc1l knockout mice show rigid muscles and resting tremor, kyphosis and a growth deficit compared with heterozygous or wild type littermate controls. Rcc1l knockout mice begin showing locomotor impairments at 3-4 months, which progress until 5-6 months of age, at which age the Rcc1l knockout mice die. The progressive motor impairments were associated with progressive and significantly reduced tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta (SNc), and dramatic loss of nigral DA projections in the striatum. Dystrophic spherical mitochondria are apparent in the soma of SNc neurons in Rcc1l knockout mice as early as 1.5-2.5 months of age and become progressively more pronounced until 5-6 months. Together, the results reveal the RCC1L protein to be essential to in vivo mitochondrial function in DA neurons. Further characterization of this mouse model will determine whether it represents a new model for in vivo study of PD, and the putative role of the human RCC1L gene as a risk factor that might increase PD occurrence and severity in humans.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    大多数先天性心脏病(CHD)病例归因于非遗传因素;然而,非遗传因素诱发CHD的潜在机制尚不清楚.糖尿病是非遗传因素之一,这项研究旨在确定受损的线粒体融合是否有助于母体糖尿病诱导的冠心病,如果线粒体融合激活剂,特立氟胺和棘球酮,可以降低糖尿病妊娠合并冠心病的发生率。我们证明母体糖尿病激活的FoxO3a增加miR-140和miR-195,进而抑制Mfn1和Mfn2,导致线粒体融合缺陷和CHD。两种线粒体融合激活剂可有效预防糖尿病妊娠中的CHD。
    Most congenital heart defect (CHD) cases are attributed to nongenetic factors; however, the mechanisms underlying nongenetic factor-induced CHDs are elusive. Maternal diabetes is one of the nongenetic factors, and this study aimed to determine whether impaired mitochondrial fusion contributes to maternal diabetes-induced CHDs and if mitochondrial fusion activators, teriflunomide and echinacoside, could reduce CHD incidence in diabetic pregnancy. We demonstrated maternal diabetes-activated FoxO3a increases miR-140 and miR-195, which in turn represses Mfn1 and Mfn2, leading to mitochondrial fusion defects and CHDs. Two mitochondrial fusion activators are effective in preventing CHDs in diabetic pregnancy.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    线粒体经历分裂和融合,这对细胞存活和癌症发展至关重要,而线粒体动力学的调节因子仍然难以捉摸。在本文中,我们发现RNAm6A加速了结直肠癌(CRC)细胞的线粒体融合。代谢组学分析和功能研究表明,m6A通过上调RRM2B-一种具有抗活性氧潜能的p53诱导型核糖核苷酸还原酶亚基来触发谷胱甘肽(GSH)的产生。这又导致CRC细胞的线粒体融合。机械上,在RRM2B的3'UTR处A1240的m6A甲基化通过与IGF2BP2结合增加其mRNA稳定性。同样,OPA1-线粒体内膜融合的必需GTP酶蛋白的编码序列(CDS)上A2212的m6A甲基化也增加了mRNA的稳定性并触发了线粒体融合。通过甲基转移酶抑制剂STM2457或dm6ACRISPR系统靶向m6A显著抑制线粒体融合。体内和临床数据证实了m6A/线粒体动力学在肿瘤生长和CRC进展中的积极作用。总的来说,m6A通过诱导GSH合成和OPA1表达促进线粒体融合,这促进了癌细胞的生长和CRC的发展。
    Mitochondria undergo fission and fusion that are critical for cell survival and cancer development, while the regulatory factors for mitochondrial dynamics remain elusive. Herein we found that RNA m6A accelerated mitochondria fusion of colorectal cancer (CRC) cells. Metabolomics analysis and function studies indicated that m6A triggered the generation of glutathione (GSH) via the upregulation of RRM2B-a p53-inducible ribonucleotide reductase subunit with anti-reactive oxygen species potential. This in turn resulted in the mitochondria fusion of CRC cells. Mechanistically, m6A methylation of A1240 at 3\'UTR of RRM2B increased its mRNA stability via binding with IGF2BP2. Similarly, m6A methylation of A2212 at the coding sequence (CDS) of OPA1-an essential GTPase protein for mitochondrial inner membrane fusion-also increased mRNA stability and triggered mitochondria fusion. Targeting m6A through the methyltransferase inhibitor STM2457 or the dm6ACRISPR system significantly suppressed mitochondria fusion. In vivo and clinical data confirmed the positive roles of the m6A/mitochondrial dynamics in tumor growth and CRC progression. Collectively, m6A promoted mitochondria fusion via induction of GSH synthesis and OPA1 expression, which facilitated cancer cell growth and CRC development.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    背景:间质睾丸间质细胞负责睾丸激素的产生,功能随着正常老化而恶化。在衰老的Leydig细胞中,线粒体类固醇生成相互作用蛋白的表达降低和线粒体功能减弱表明,线粒体动力学在维持适当的睾酮水平中起作用。视神经萎缩1(OPA1)蛋白调节许多细胞类型的线粒体动力学和cr形成。先前的研究表明,在功能失调的Leydig细胞中增加OPA1表达可以恢复线粒体功能,并将雄激素产生恢复到健康Leydig细胞中的水平。这些发现表明,线粒体动力学可能是改善衰老男性睾丸激素水平降低的有希望的目标。方法:我们使用12月龄大鼠,探讨线粒体动力学与睾丸间质细胞功能之间的关系。用细胞通透性线粒体融合启动子4-氯-2-(1-(2-(2,4,6-三氯苯基)肼基)乙基)苯酚(线粒体融合启动子M1)离体处理来自老年大鼠的Leydig细胞,从而增强线粒体肾小管网络的形成。并行,在分离Leydig细胞之前,用2mg/kg/天M1处理大鼠6周。结果:离体M1处理的细胞通过透射电子显微镜显示增强的线粒体肾小管网络形成,增强睾丸间质细胞线粒体完整性,改善线粒体功能,与对照组相比,睾酮的生物合成更高。然而,用M1对老年大鼠的体内治疗不仅无法重新建立年轻大鼠的睾丸激素水平,它还导致睾酮水平进一步降低和细胞凋亡增加,提示睾丸中的M1毒性。体内M1毒性似乎是组织特异性的,however.结论:促进线粒体融合可能是随着衰老增强细胞健康和福祉的一种方法。但需要更多的调查.我们的发现表明,当仔细调节时,融合启动子可能会提高老化的Leydig细胞的生产率。
    Background: The interstitial testicular Leydig cells are responsible for the production of testosterone, which functionally deteriorate with normal aging. Decreased expression of mitochondrial steroidogenic interactome proteins and diminished mitochondrial function in aging Leydig cells suggest that mitochondrial dynamics play a role in maintaining adequate levels of testosterone. Optic atrophy 1 (OPA1) protein regulates mitochondrial dynamics and cristae formation in many cell types. Previous studies showed that increasing OPA1 expression in dysfunctional Leydig cells restored mitochondrial function and recovered androgen production to levels found in healthy Leydig cells. These findings suggested that mitochondrial dynamics may be a promising target to ameliorate diminished testosterone levels in aging males. Methods: We used twelve-month-old rats to explore the relationship between mitochondrial dynamics and Leydig cell function. Isolated Leydig cells from aged rats were treated ex vivo with the cell-permeable mitochondrial fusion promoter 4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl)hydrazono)ethyl) phenol (mitochondrial fusion promoter M1), which enhances mitochondrial tubular network formation. In parallel, rats were treated with 2 mg/kg/day M1 for 6 weeks before Leydig cells were isolated. Results: Ex vivo M1-treated cells showed enhanced mitochondrial tubular network formation by transmission electron microscopy, enhanced Leydig cell mitochondrial integrity, improved mitochondrial function, and higher testosterone biosynthesis compared to controls. However, in vivo treatment of aged rats with M1 not only failed to re-establish testosterone levels to that of young rats, it also led to further reduction of testosterone levels and increased apoptosis, suggesting M1 toxicity in the testis. The in vivo M1 toxicity seemed to be tissue-specific, however. Conclusion: Promoting mitochondrial fusion may be one approach to enhancing cell health and wellbeing with aging, but more investigations are warranted. Our findings suggest that fusion promoters could potentially enhance the productivity of aged Leydig cells when carefully regulated.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    在苏木精和伊红(H&E)染色期间,用酒精溶解组织切片中的脂滴会导致肿瘤细胞在显微镜下看起来像清晰的肥皂泡,是肾透明细胞癌的重要病理特征。线粒体动力学已被报道与脂质代谢和肿瘤的发展密切相关。然而,线粒体动力学与ccRCC脂质代谢重编程之间的关系还有待进一步探讨。我们进行了生物信息学分析,以确定调节肿瘤和正常组织之间线粒体动力学差异表达的关键基因,并进行免疫组织化学和Westernblot确认。确定目标后,我们创建了稳定的ccRCC细胞系来测试靶基因对线粒体形态的影响,培养细胞和异种移植模型中的肿瘤发生,和脂质代谢的概况。发现mitofusin2(MFN2)在ccRCC组织中下调,并与ccRCC患者的不良预后有关。MFN2抑制线粒体片段化,扩散,迁移,ccRCC细胞的侵袭和异种移植肿瘤的生长。此外,MFN2影响脂质代谢并减少ccRCC细胞中脂滴的积累。MFN2可能通过中断细胞脂质代谢和减少脂滴积累来抑制ccRCC患者的疾病进展并改善预后。
    Dissolving the lipid droplets in tissue section with alcohol during a hematoxylin and eosin (H&E) stain causes the tumor cells to appear like clear soap bubbles under a microscope, which is a key pathological feature of clear cell renal cell carcinoma (ccRCC). Mitochondrial dynamics have been reported to be closely associated with lipid metabolism and tumor development. However, the relationship between mitochondrial dynamics and lipid metabolism reprogramming in ccRCC remains to be further explored. We conducted bioinformatics analysis to identify key genes regulating mitochondrial dynamics differentially expressed between tumor and normal tissues and immunohistochemistry and Western blot to confirm. After the target was identified, we created stable ccRCC cell lines to test the impact of the target gene on mitochondrial morphology, tumorigenesis in culture cells and xenograft models, and profiles of lipid metabolism. It was found that mitofusin 2 (MFN2) was downregulated in ccRCC tissues and associated with poor prognosis in patients with ccRCC. MFN2 suppressed mitochondrial fragmentation, proliferation, migration, and invasion of ccRCC cells and growth of xenograft tumors. Furthermore, MFN2 impacted lipid metabolism and reduced the accumulation of lipid droplets in ccRCC cells. MFN2 suppressed disease progression and improved prognosis for patients with ccRCC possibly by interrupting cellular lipid metabolism and reducing accumulation of lipid droplets.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    坏死,一种坏死的形式,和线粒体动力学的改变,线粒体分裂和融合的协调过程,与心血管疾病的发病机制有关。本研究旨在确定线粒体形态在TNFα和zVAD(TNF/zVAD)联合诱导的H9c2细胞的经典坏死中的作用。大鼠心肌细胞。线粒体形态的时程分析显示,添加TNF/zVAD后,线粒体最初缩短,然后恢复其长度,在TNF/zVAD处理的细胞中,在12小时具有细长线粒体的细胞比例大于未处理的细胞(16.3±0.9%vs.8.0±1.2%)。dynamin相关蛋白1(Drp1)和裂变1,用Drp-1抑制剂Mdivi-1治疗,对TNF/zVAD诱导的坏死没有影响。相比之下,TNF/zVAD诱导的坏死通过mitofusin1/2(Mfn1/2)和视神经萎缩1(Opa1)的敲低而减弱,对线粒体融合不可或缺的蛋白质,Mdivi-1治疗不能消除坏死的衰减。TGFβ活化激酶(TAK1)的表达,RIP1活性的负调节剂,上调,TNF/zVAD诱导的RIP1-Ser166磷酸化,RIP1活性指数,通过Mfn1/2或Opa1的敲低而减轻。药理学TAK1抑制减弱了Mfn1/2和Opa1敲低提供的保护。总之,抑制线粒体融合增加TAK1表达,通过抑制RIP1活性导致经典坏死的衰减。
    Necroptosis, a form of necrosis, and alterations in mitochondrial dynamics, a coordinated process of mitochondrial fission and fusion, have been implicated in the pathogenesis of cardiovascular diseases. This study aimed to determine the role of mitochondrial morphology in canonical necroptosis induced by a combination of TNFα and zVAD (TNF/zVAD) in H9c2 cells, rat cardiomyoblasts. Time-course analyses of mitochondrial morphology showed that mitochondria were initially shortened after the addition of TNF/zVAD and then their length was restored, and the proportion of cells with elongated mitochondria at 12 h was larger in TNF/zVAD-treated cells than in non-treated cells (16.3 ± 0.9% vs. 8.0 ± 1.2%). The knockdown of dynamin-related protein 1 (Drp1) and fission 1, fission promoters, and treatment with Mdivi-1, a Drp-1 inhibitor, had no effect on TNF/zVAD-induced necroptosis. In contrast, TNF/zVAD-induced necroptosis was attenuated by the knockdown of mitofusin 1/2 (Mfn1/2) and optic atrophy-1 (Opa1), proteins that are indispensable for mitochondrial fusion, and the attenuation of necroptosis was not canceled by treatment with Mdivi-1. The expression of TGFβ-activated kinase (TAK1), a negative regulator of RIP1 activity, was upregulated and the TNF/zVAD-induced RIP1-Ser166 phosphorylation, an index of RIP1 activity, was mitigated by the knockdown of Mfn1/2 or Opa1. Pharmacological TAK1 inhibition attenuated the protection afforded by Mfn1/2 and Opa1 knockdown. In conclusion, the inhibition of mitochondrial fusion increases TAK1 expression, leading to the attenuation of canonical necroptosis through the suppression of RIP1 activity.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

  • 文章类型: Journal Article
    线粒体负责细胞ATP的产生,细胞溶质钙水平的调节,以及通过释放激活半胱天冬酶所必需的辅因子来组织许多凋亡蛋白。这种功能适应性水平只能通过复杂的结构对齐来实现。线粒体的形态在整个时间内不会保持不变;相反,由于被称为聚变和裂变的过程,它经历了变化。FZO在苍蝇,酵母中的Fzo1,哺乳动物中的mitofusins负责管理线粒体外膜融合过程,而酵母中的Mgm1和哺乳动物中的视神经萎缩1负责管理线粒体内膜融合过程。融合过程由两个阶段组成。MFN1,一种位于线粒体外膜上的GTP酶,参与连接附近线粒体的过程,维持线粒体膜的电位,和凋亡。本文提供了有关MFN1在活体生物中发现的各种细胞和器官中的功能的具体信息。根据文献综述的发现,MFN1在许多疾病和器官系统中起着重要作用;然而,该蛋白质在其他疾病模型和细胞类型中的功能必须在不久的将来进行研究,以便它可以被选择为具有治疗和诊断潜力的有希望的标记。总的来说,这篇综述的主要发现强调了mitofusin(MFN1)在调节线粒体动力学及其在各种疾病中的意义中的关键作用,包括神经退行性疾病,心血管疾病,和代谢综合征。我们的综述确定了MFN1信号通路中的新治疗靶标,并强调了MFN1调节作为治疗线粒体相关疾病的有希望的策略的潜力。此外,该综述呼吁进一步研究MFN1的分子机制,以开启临床干预的新途径,强调需要针对MFN1功能障碍的靶向治疗。
    The mitochondria are responsible for the production of cellular ATP, the regulation of cytosolic calcium levels, and the organization of numerous apoptotic proteins through the release of cofactors necessary for the activation of caspases. This level of functional adaptability can only be attained by sophisticated structural alignment. The morphology of the mitochondria does not remain unchanged throughout time; rather, it undergoes change as a result of processes known as fusion and fission. Fzo in flies, Fzo1 in yeast, and mitofusins in mammals are responsible for managing the outer mitochondrial membrane fusion process, whereas Mgm1 in yeast and optic atrophy 1 in mammals are responsible for managing the inner mitochondrial membrane fusion process. The fusion process is composed of two phases. MFN1, a GTPase that is located on the outer membrane of the mitochondria, is involved in the process of linking nearby mitochondria, maintaining the potential of the mitochondrial membrane, and apoptosis. This article offers specific information regarding the functions of MFN1 in a variety of cells and organs found in living creatures. According to the findings of the literature review, MFN1 plays an important part in a number of diseases and organ systems; nevertheless, the protein\'s function in other disease models and cell types has to be investigated in the near future so that it can be chosen as a promising marker for the therapeutic and diagnostic potentials it possesses. Overall, the major findings of this review highlight the pivotal role of mitofusin (MFN1) in regulating mitochondrial dynamics and its implications across various diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes. Our review identifies novel therapeutic targets within the MFN1 signaling pathways and underscores the potential of MFN1 modulation as a promising strategy for treating mitochondrial-related diseases. Additionally, the review calls for further research into MFN1\'s molecular mechanisms to unlock new avenues for clinical interventions, emphasizing the need for targeted therapies that address MFN1 dysfunction.
    导出

    更多引用

    收藏

    翻译标题摘要

    我要上传

       PDF(Pubmed)

公众号