更新于：2024-11-01

MFN1

更新于：2024-11-01

基本信息

别名

FLJ20693、Fzo homolog、MFN1

+ [3]

简介

Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion (PubMed:12475957, PubMed:12759376, PubMed:27920125, PubMed:28114303). Membrane clustering requires GTPase activity (PubMed:27920125). It may involve a major rearrangement of the coiled coil domains (PubMed:27920125, PubMed:28114303). Mitochondria are highly dynamic organelles, and their morphology is determined by the equilibrium between mitochondrial fusion and fission events (PubMed:12475957, PubMed:12759376). Overexpression induces the formation of mitochondrial networks (in vitro) (PubMed:12759376). Has low GTPase activity (PubMed:27920125, PubMed:28114303).

关联

项与 MFN1 相关的药物

S89

靶点

MFN1

作用机制

MFN1激动剂

在研机构

中国科学院昆明植物研究所 [+2]

原研机构

中国科学院生物物理研究所

在研适应症

线粒体病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MFN1 相关的临床结果

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100 项与 MFN1 相关的转化医学

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0 项与 MFN1 相关的专利（医药）

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980

项与 MFN1 相关的文献（医药）

2025-01-01·Journal of Ethnopharmacology

Study on the role of Dihuang Yinzi in regulating the AMPK/SIRT1/PGC-1α pathway to promote mitochondrial biogenesis and improve Alzheimer's disease

Article

作者: He, Wenbin ; Han, Cheng ; Li, Qinqing ; Zhang, Zheng ; Hou, Jiangqi ; Zhang, Junlong ; Du, Yuzhong ; Zhu, Yousong ; Zhao, Qiong ; Qin, Yali ; Zhu, Chao

ETHNOPHARMACOLOGICAL RELEVANCEDihuang Yinzi (DHYZ) is a classic prescription in traditional Chinese medicine. Its therapeutic effect on Alzheimer's disease (AD) has been widely validated. However, the underlying molecular mechanisms of DHYZ in AD treatment remain unclear and require further research.AIM OF THE STUDYElucidating DHYZ's promotion of mitochondrial biogenesis through the AMPK/SIRT1/PGC-1α pathway improves neuronal loss, mitochondrial damage, and memory deficits in AD.MATERIALS AND METHODSAdministering DHYZ by gavage to SAMP8 mice, after completing behavioral tests, the effects of DHYZ on hippocampal neuron loss and mitochondrial structural damage in AD model mice were assessed using Nissl staining and transmission electron microscopy. Western blot was used to detect the expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, mitochondrial fusion protein MFN2, and mitochondrial fission proteins DRP1 and FIS1. At the same time, immunofluorescence (IF) was employed to measure the relative fluorescence intensity of mitochondrial fusion protein MFN1. After determining the optimal dose of DYHZ for treating AD, we conducted mechanistic studies. By intraperitoneally injecting SAMP8 mice with the AMPK inhibitor (Compound C) to inhibit AMPK protein expression and subsequently treating them with DHYZ, the impact of DHYZ on hippocampal neurons in AD model mice was evaluated using Nissl and hematoxylin-eosin staining. Western blot was used to detect the protein expression of AMPK, p-AMPK, SIRT1, PGC-1α, NRF1, and TFAM. In contrast, IF was used to measure the relative fluorescence intensity of PGC-1α, NRF1, and TFAM proteins in the hippocampal CA1 region.RESULTSDHYZ significantly improved AD model mice's cognitive impairment and memory deficits and mitigated hippocampal neuron loss and degeneration. Additionally, it ameliorated mitochondrial morphological structures. DHYZ upregulated the protein expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, and mitochondrial fusion proteins MFN1 and MFN2 while inhibiting the expression of mitochondrial fission proteins DRP1 and FIS1. Further studies revealed that DHYZ could upregulate the expression of the AMPK/SIRT1/PGC-1α pathway proteins and their downstream proteins NRF1 and TFAM.CONCLUSIONDHYZ promotes mitochondrial biogenesis by activating the AMPK/SIRT1/PGC-1α signaling pathway, thereby improving memory deficits, neuronal loss, and mitochondrial dysfunction in AD.

2024-12-31·Journal of the International Society of Sports Nutrition

Oral post-exercise garlic extract supplementation enhances glycogen replenishment but does not up-regulate mitochondria biogenesis mRNA expression in human-exercised skeletal muscle

Article

作者: Tsai, Tsen-Wei ; Bernard, Jeffrey R ; Chang, Chia-Chen ; Tsao, Jung-Piao ; Liao, Su-Fen ; Cheng, I-Shiung

PURPOSEGarlic extract (GA) is purported to enhance antioxidant and anti-inflammatory activity and glucose regulation in humans. The present study investigated the effects of post-exercise GA supplementation on GLUT4 expression, glycogen replenishment, and the transcript factors involved with mitochondrial biosynthesis in exercised human skeletal muscle.METHODSThe single-blinded crossover counterbalanced study was completed by 12 participants. Participants were randomly divided into either GA (2000 mg of GA) or placebo trials immediately after completing a single bout of cycling exercise at 75% Maximal oxygen uptake (VO_2max) for 60 minutes. Participants consumed either GA (2000 mg) or placebo capsules with a high glycemic index carbohydrate meal (2 g carb/body weight) immediately after exercise. Muscle samples were collected at 0-h and 3-h post-exercise. Muscle samples were used to measure glycogen levels, GLUT4 protein expression, as well as transcription factors for glucose uptake, and mitochondria biogenesis. Plasma glucose, insulin, glycerol, non-esterified fatty acid (NEFA) concentrations, and respiratory exchange ratio (RER) were also analyzed during the post-exercise recovery periods.RESULTSSkeletal muscle glycogen replenishment was significantly elevated during the 3-h recovery period for GA concurrent with no difference in GLUT4 protein expression between the garlic and placebo trials. PGC1-α gene expression was up-regulated for both GA and placebo after exercise (p < 0.05). Transcript factors corresponding to muscle mitochondrial biosynthesis were significantly enhanced under acute garlic supplementation as demonstrated by TFAM and FIS1. However, the gene expression of SIRT1, ERRα, NFR1, NFR2, MFN1, MFN2, OPA1, Beclin-1, DRP1 were not enhanced, nor were there any improvements in GLUT4 expression, following post-exercise garlic supplementation.CONCLUSIONAcute post-exercise garlic supplementation may improve the replenishment of muscle glycogen, but this appears to be unrelated to the gene expression for glucose uptake and mitochondrial biosynthesis in exercised human skeletal muscle.

2024-12-16·Animal Biotechnology

Vitamin C enhances the in vitro development of early porcine embryos by improving mitochondrial function

Article

作者: Qiu, Peng ; She, Liu ; Shi, Deshun ; Wang, Lei ; Qi, Yunjia ; Han, Qin ; Zhang, Yunchuan ; Lv, Meiyun ; Luo, Chan

Mammalian embryos often suffer from oxidative stress in vitro, as the oxygen in the atmosphere is higher than that in the oviductal environment. Vitamin C (Vc) has been proven to enhance early embryonic development in vitro, but the underlying mechanism remains unclear. In this study, we investigated the pathways of action by which Vc promotes the in vitro development of porcine embryos. Comparative analysis of in vitro and in vivo gene expression profiles of morula found that most of the differentially expressed genes were enriched in pathways related to mitochondrial function. The addition of 12.5 μg/mL Vc to the culture medium significantly increased blastocyst production in a dose- and duration-dependent manner. Moreover, ROS levels were significantly higher in embryos cultured in the air (21% oxygen) than cultured in a hypoxic condition (5% oxygen) and were reduced by Vc supplementation. Vc also significantly increased the mitochondrial membrane potential levels and the expression levels of mitochondrial function-related genes (MFN1 and OPA1) and TCA cycle-related genes (PDHA1 and OGDH) in embryos cultured in vitro. These results suggest that the addition of Vc to the in vitro culture medium can increase the developmental potential and improve the mitochondrial function of early porcine embryos.

项与 MFN1 相关的新闻（医药）

2023-12-14

·今日头条

新进展！南开大学/天津医科大学等合作发文：支原体促进肝癌发生和发展的新机制

本文为转化医学网原创，转载请注明出处作者：Jerry 导读：肝细胞癌(HCC)的发生和发展与病毒感染和肠道细菌密切相关。然而，对HCC肿瘤微环境中的细菌知之甚少。近日，天津南开大学/天津医科大学肿瘤医院/天津国际生物医药联合研究院研究人员合作在期刊《Cell Reports》上发表了题为“Intratumor Mycoplasma promotes the initiation and progression of hepatocellular carcinoma”的研究论文，研究人员发现瘤内猪鼻支原体通过增强核倍性促进HCC的发生和发展。研究结果表明，支原体感染促进病理性多倍体化，并提示用抗生素清除支原体或调节线粒体动力学可能具有治疗HCC的潜力。 https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01575-9#%20 研究背景 01 支原体是介于细菌和病毒之间的最小的原核微生物，可以在无生命的培养基中生长。猪鼻支原体、人支原体和生殖支原体与癌症密切相关。早在1965年，Paton等人就报道口腔支原体可引起人类二倍体细胞系WI-38染色体异常。由于各种支原体的污染会显著影响体外细胞培养，全球科学家已经达成共识，在实验室中消除支原体污染。体内研究已经发现了支原体在各种肿瘤类型中存在并带来影响，如胃癌、乳腺癌、前列腺癌、胰腺癌、卵巢癌和宫颈癌。许多临床病例报告也发现支原体在鼻多晶状体肉瘤、口腔癌和淋巴瘤中。尽管有这些关于肝细胞癌(HCC)和支原体之间关系的报道，一些关键问题仍未得到解决，比如病原种类的鉴定、感染途径和临床前研究。多倍体细胞很早就在肿瘤中被发现和描述。早在1974年，Aggarwal等人就发现顺铂可抑制细胞分裂产生多倍体巨细胞。迄今为止，多倍体细胞已在各种癌症中被观察到，如胰腺癌、宫颈癌、支气管癌和结肠癌。大约30%的实体瘤具有多倍体或近多倍体核型。各种机制，如内复制、细胞分裂失败、细胞融合、细胞衰老抵抗、环境应激包括缺氧、抗有丝分裂药物、激酶抑制剂治疗和放疗，可以促进多倍体细胞的发生。然而，支原体感染在多倍体细胞形成中的作用从未被研究过。研究进展 02 研究人员建立了DEN诱导的肝癌模型，研究猪鼻支原体在肝癌发生中的作用。三组小鼠(n = 6)给予DEN，其中两组小鼠在给药4周后感染猪鼻支原体。感染支原体14周后，给其中一组小鼠注射AZM，AZM是一种用于清除支原体的抗生素(图1A)。生存分析表明，AZM可以显著恢复支原体感染导致的生存时间缩短(图1B)。H&E切片的肝内结节和肺转移结节数量增加，AZM治疗逆转了猪鼻支原体感染引起的肿瘤结节数量增加和肺转移(图1C-E)。研究人员将一株荧光素酶标记的SK-Hep1细胞株原位植入肝脏，研究猪鼻支原体在HCC进展中的作用。采用小动物活体成像测量肿瘤大小。与DEN诱导的HCC模型的结果一致，在体内，猪鼻支原体感染促进了肿瘤的生长，但AZM给药减缓了肿瘤的生长(图1F和1G)。总之，猪鼻支原体感染促进了肝癌的发生和发展。图1：在小鼠模型中，猪鼻支原体感染促进HCC的发展研究结论 03 总之，支原体感染独立于其他HCC危险因素。猪鼻支原体广泛存在于HCC肿瘤组织中，可通过肝胰壶腹逆行感染肝脏。体内外模型研究表明，支原体感染促进HCC的发生和进展，并与核多倍体和结构密切相关。进一步的机制研究证实，猪鼻支原体可以通过m6a依赖的方式抑制MFN1的表达，入侵细胞，劫持线粒体，并促进线粒体分裂。调节线粒体动力学可抑制肿瘤干细胞多倍体形成和干性。这一发现也支持线粒体和细胞核之间相互作用的理论。干扰线粒体动力学可能是一种靶向肿瘤干细胞的策略。参考资料： https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01575-9#%20 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布）点击对应文字查看详情

临床研究临床结果

2023-10-09

·生物探索

改善癌症免疫疗法疗效的新策略

代谢适应性对于T细胞的活力至关重要，而这在很大程度上取决于线粒体的行为。肿瘤浸润的T细胞内线粒体行为的性质尚不清楚。2023年9月22日，中山大学韩辉，高嵩和北京大学白凡共同通讯在Science Immunology（IF=25）在线发表题为“Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors”的研究论文，该研究展示了线粒体融合素-2（MFN2）的表达与多种癌症的预后呈正相关。在CD8+ T细胞中遗传消融Mfn2抑制了线粒体代谢和功能，促进了肿瘤的发展。在肿瘤浸润的CD8+ T细胞中，MFN2通过与内质网嵌入的Ca2+-ATP酶SERCA2相互作用，促进线粒体所需的高效线粒体Ca2+流入，增强了线粒体-内质网（ER）接触。MFN2刺激了SERCA2的ER Ca2+回收活性，从而防止过多的线粒体Ca2+积累和细胞凋亡。通过增加CD8+ T细胞中的MFN2来提高线粒体-ER接触，可以提高癌症免疫疗法的效果。因此，该研究揭示了一个调节肿瘤浸润的CD8+ T细胞代谢适应性的缓冲机制，并突显了通过增加MFN2表达以优化T细胞功能的治疗潜力。尽管在癌症免疫疗法中广泛应用了采用肿瘤反应性肿瘤浸润淋巴细胞（TILs）的移植和免疫检查点阻断（ICB），但耐久和完全的治疗反应仅在临床病例的一小部分中观察到，尤其是在固体恶性肿瘤中。T细胞在肿瘤微环境（TME）内失去效应细胞功能是T细胞免疫疗法失败的主要原因之一。新出现的证据强调了代谢适应性在编程T细胞功能和命运方面的重要性。与肿瘤细胞的营养竞争限制了TILs的代谢能力，有助于免疫逃逸。异常的线粒体表型，包括减少的总质量和活性氧（ROS）水平、增加的去极化和碎片化形态，是疲劳的CD8+ TILs的特征。在TME内低血糖条件下，通过脂肪酸氧化（FAO）驱动的氧化磷酸化（OXPHOS）对TILs的效应功能和生存至关重要。通过矫正TILs的线粒体表型来进行代谢重塑是加强T细胞免疫疗法的临床疗效的有前途的策略。线粒体融合素（MFNs）是负责线粒体融合的类似动力蛋白三磷酸酶（GTPases），这是增强OXPHOS能力的基本事件。哺乳动物有两种MFNs，MFN1和MFN2，它们在序列相似性上共享80%的相似性，并在催化线粒体外膜融合方面存在一定程度的冗余。在体外，MFN2的脂质体系结效率高于MFN1，而MFN2介导线粒体（mito）-内质网（ER）的连接，尽管其基本机制仍然存在争议。Mito-ER接触使ER到线粒体的Ca2+流动成为可能，这是激活Krebs循环的关键酶以调控线粒体腺苷5'-三磷酸（ATP）产生的必要过程。总体而言，MFN2通过控制线粒体行为而充当代谢中枢。MFN2的突变或异常表达与多种人类疾病的发病有关，包括神经肌肉疾病、心脏代谢性疾病和癌症。在肿瘤微环境内，CD8+ T细胞在被激活后表现出MFN2的上调，并与更好的效应功能、氧化磷酸化（OXPHOS）和患者生存率相关。线粒体动力学在不同激活和功能状态的CD8+ T细胞的代谢特征中起着关键作用。线粒体融合在记忆CD8+ T细胞中受到青睐，用于细胞分化和生存。在患有明显肾细胞肾癌（ccRCC）的患者的CD8+ TILs中观察到了干扰的线粒体融合。CD8+ TILs中的线粒体去极化和线粒体自噬引发了疲劳表型。平衡的线粒体动力学对肿瘤浸润的自然杀伤细胞（NK细胞）和巨噬细胞的重要性也已经得到证明。在体外模型中，强化效应T细胞中的线粒体融合会导致记忆T细胞特性，并促进抗肿瘤能力。通过磷脂酰肌醇-3-激酶δ/γ（PI3Kδ/γ）抑制剂duvelisib治疗，可以增加CD8+ 嵌合抗原受体T细胞中的MFN2表达，从而增强其细胞毒性和干细胞性。Mito-ER接触对于记忆CD8+ T细胞的快速召回反应至关重要。最近的研究表明，亚油酸通过增强mito-ER接触来增强CD8+ T细胞的代谢适应性和抗肿瘤活性。然而，关于CD8+ TILs中线粒体融合的性质知之甚少。此外，CD8+ TILs中mito-ER接触的功能和调节机制也尚未被充分了解。该研究发现MFN2介导mito-ER接触以维持线粒体Ca2+稳态，从而促进CD8+ TILs的代谢适应性和效应功能。通过增加CD8+ T细胞中的MFN2以增强mito-ER接触，可以改善癌症免疫疗法的疗效。文章来源“iNature”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

免疫疗法细胞疗法

2023-03-10

·生物谷

研究揭示小分子促进线粒体融合并修补线粒体损伤的新机制

粉花绣线菊复合群包含七个变种，为我国特有。在早期的化学与生物学研究基础上，中国科学院昆明植物研究所郝小江团队开展了其特征性二萜及二萜生物碱的生物功能挖掘，相继揭示了部分化学成分可促进线粒体融合粉花绣线菊复合群包含七个变种，为我国特有。在早期的化学与生物学研究基础上，中国科学院昆明植物研究所郝小江团队开展了其特征性二萜及二萜生物碱的生物功能挖掘，相继揭示了部分化学成分可促进线粒体融合、特异性抑制Wnt信号通路、通过非Bax/Bak依赖的线粒体途径诱导细胞凋亡、抑制原癌基因Fli-1表达等新作用机制。近日，该团队与南开大学陈佺团队、中科院生物物理研究所胡俊杰团队合作，在Nature Chemical Biology以长文形式在线发表题为Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction的研究论文，报道了绣线菊二萜生物碱的衍生物S89能够特异性激活线粒体融合蛋白MFN1并修补多类线粒体损伤。线粒体是调控细胞能量稳态和命运决定的中心，可通过不断融合和分裂维持其正常功能，其中线粒体融合蛋白1（MFN1）和MFN2是介导线粒体外膜融合的动力蛋白样GTP酶。而线粒体分裂与融合失衡导致的过度碎片化是人类诸多疾病与衰老的重要标志之一，如MFN2的突变导致腓骨肌萎缩症（CMT2A）等多种遗传性神经退行性疾病。该研究以线粒体融合的筛选体系为基础，合成并筛选了数十个该类衍生物，发现S89可直接靶向MFN1，并通过MFN1而不是MFN2促进GTP水解和线粒体融合。S89分子通过缓解MFN1自身抑制作用，并在MFN2缺陷时增强内源性MFN1的活性，从而恢复CMT2A患者来源细胞的线粒体功能。S89还通过防止线粒体损伤保护小鼠心脏组织免受缺血/再灌注损伤。因此，促进线粒体融合的小分子化合物将有助于治疗线粒体相关疾病，如代谢、免疫和神经系统疾病等，是生命科学和生物医学研究备受关注的前沿方向。相关研究工作得到国家自然科学基金、国家重点研发计划、中科院战略性先导科技专项（B类）、中科院稳定支持基础研究领域青年团队计划等的支持。研究揭示小分子促进线粒体融合并修补线粒体损伤的新机制