更新于：2024-05-01

MT-ATP6

mitochondrially encoded ATP synthase membrane subunit 6

更新于：2024-05-01

基本信息

别名

ATP synthase 6、ATP synthase subunit a、ATP6

+ [11]

简介

Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Key component of the proton channel; it may play a direct role in the translocation of protons across the membrane.

关联

项与 MT-ATP6 相关的药物

CCCh-1005-TPP

靶点-

作用机制

MT-ATP6 调节剂

在研机构

Shin Nippon Biomedical Laboratories, Ltd.

原研机构

Shin Nippon Biomedical Laboratories, Ltd.

在研适应症

肿瘤 [+1]

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 MT-ATP6 相关的临床结果

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100 项与 MT-ATP6 相关的转化医学

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0 项与 MT-ATP6 相关的专利（医药）

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3,194

项与 MT-ATP6 相关的文献（医药）

2024-02-23·Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

Two-stage association study of mitochondrial DNA variants in allergic rhinitis.

Article

作者: Huajie Yuan ; Lingling Wang ; Song Wang ; Linge Li ; Qingping Liu ; Yan Wang ; Yuping Yang ; Hua Zhang

BACKGROUND:

Correlations between mitochondrial DNA (mtDNA) and allergic rhinitis (AR) have not been reported before. This study aimed to better understand the mitochondrial genome profile with AR and to investigate the associations between AR in China and the mitochondrial genome at a single variant and gene level.

METHODS:

Mitochondrial sequencing was conducted on a total of 134 unrelated individual subjects (68 patients with AR, 66 healthy controls) at discovery stage. Heteroplasmy was analyzed using the Mann-Whitney U test. Sequence kernel association tests (SKAT) were conducted to study the association between mitochondrial genes and AR. Single-variant analysis was performed using logistic regression analysis and further validated in 120 subjects (69 patients with AR, 51 healthy controls). Candidate genes were further explored based on differences in mRNA and protein abundance in nasal mucosal tissue.

RESULTS:

In the discovery stage, 886 variants, including 836 SNV and 50 indels, were identified with mitochondrial sequencing. No statistically significant differences were identified for the mitochondrial heteroplasmy or SKAT analysis between these two groups after applying a Boferroni correction. One nonsynonymous variants, rs3135028 (MT8584.G/A) in ATP6, was related to a reduced risk of AR in both the discovery and validation cohorts. Furthermore, mRNA levels of MT-ATP6 in nasal mucosal tissue were significantly lower in AR individuals than in controls (P < 0.05).

CONCLUSIONS:

In a two-stage analysis of associations between AR and mtDNA variations, mitochondrial gene maps of Chinese patients with AR indicated that the ATP6 gene was probably associated with AR at the single-variant level.

2024-02-13·International journal of molecular sciences

Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies.

Review

作者: Valentina Del Dotto ; Francesco Musiani ; Alessandra Baracca ; Giancarlo Solaini

Mitochondrial ATP synthase (Complex V) catalyzes the last step of oxidative phosphorylation and provides most of the energy (ATP) required by human cells. The mitochondrial genes MT-ATP6 and MT-ATP8 encode two subunits of the multi-subunit Complex V. Since the discovery of the first MT-ATP6 variant in the year 1990 as the cause of Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome, a large and continuously increasing number of inborn variants in the MT-ATP6 and MT-ATP8 genes have been identified as pathogenic. Variants in these genes correlate with various clinical phenotypes, which include several neurodegenerative and multisystemic disorders. In the present review, we report the pathogenic variants in mitochondrial ATP synthase genes and highlight the molecular mechanisms underlying ATP synthase deficiency that promote biochemical dysfunctions. We discuss the possible structural changes induced by the most common variants found in patients by considering the recent cryo-electron microscopy structure of human ATP synthase. Finally, we provide the state-of-the-art of all therapeutic proposals reported in the literature, including drug interventions targeting mitochondrial dysfunctions, allotopic gene expression- and nuclease-based strategies, and discuss their potential translation into clinical trials.

2024-02-10·Talanta

A dual-signal amplification strategy based on rolling circle amplification and APE1-assisted amplification for highly sensitive and specific miRNA analysis for early diagnosis of alzheimer's disease.

Article

作者: Juan Xie ; Jing Chen ; Ya Zhang ; Changhong Li ; Piao Liu ; Wen-Jun Duan ; Jin-Xiang Chen ; Jun Chen ; Zong Dai ; Minmin Li

MicroRNA (miRNA) is involved in the progression of Alzheimer's disease (AD) and emerges as a promising AD biomarker and therapeutic target. Therefore, there is an urgent need to develop convenient and precise miRNA detection methods for AD diagnosis. Herein, a dual-signal amplification strategy based on rolling circle amplification and APE1-assisted amplification for miRNA analysis for early diagnosis of AD was proposed. The strategy consisted of dumbbell-shaped probe (DP) as amplification template and a reporter probe (RP) with an AP site modification. In the presence of the target miRNA, the miRNAs bound to the toehold domain of DP and DP was activated into a circular template. Then, RCA reaction was triggered, producing a large number of long-stranded products containing repeated sequences. After RCA, APE1 enzyme recognized and removed AP site in the complex of RCA/RP products. By coupling RCA with APE1-assisted amplification, this method has high sensitivity with the limit of detection (LOD) of 1.82 fM. Moreover, by using DP as template for RCA reaction, high specificity can be achieved. By detecting miR-206 in serum using this method, the expression of miR-206 can be accurately distinguished between AD patients and healthy individuals, indicating that this method has broad application prospects in clinical diagnosis.

项与 MT-ATP6 相关的新闻（医药）

2024-02-27

·生物探索

Cell | 8年磨一剑！中山大学魏来/张峰/魏泓等团队合作揭示肠道细菌可导致失明的机制

引言CRB1 基因与视网膜变性有关，最常见的是先天性黑内障(LCA)和视网膜色素变性(RP)。2024年2月26日，中山大学魏来、张峰、魏泓及伦敦大学Richard RW Lee共同通讯在Cell在线发表题为“CRB1-associated retinal degeneration is dependent on bacterial translocation from the gut”的研究论文，经过8年的研究发现眼睛与肠道存在令人意想不到的关联。虽然正常的CRB1表达在视网膜色素上皮和结肠肠细胞的顶端连接复合体中富集，但CRB1突变抑制了这两个部位的表达。Rd8小鼠外周血视网膜屏障和结肠肠上皮屏障随之受损，导致肠道细菌从下胃肠道(GI)转移到视网膜，导致继发性视网膜变性。无论是系统地消耗细菌，还是重新引入正常Crb1表达，都可以在不逆转视网膜屏障破坏的情况下挽救Rd8突变相关的视网膜变性。该研究明了Cb1突变相关视网膜变性的发病机制，并表明抗菌药物有可能治疗这种毁灭性的致盲疾病。遗传性视网膜变性是工业化国家工作年龄人群失明的最常见原因。它们是一组异质性疾病，具有250多个相关基因和广泛的临床表型，其发病通常从出生到成年早期不同，对患者及其家庭具有终身影响。CRB1基因突变可引起视网膜变性，包括Leber先天性黑内障(LCA)和色素性视网膜炎(RP)。总体而言，它们在全球范围内占LCA的10%-15%和RP的4%，在西班牙，CRB1是所有LCA和RP患者中最常见的突变基因。因此，对抗Crb1相关视网膜变性的有效治疗有可能帮助减轻遗传性视网膜失明的负担。先前基于有限数量组织数据的研究得出结论，CRB1/ CRB1基因仅在人类和小鼠的眼睛和大脑中表达，特别是在神经上皮细胞中。Crb1在视网膜和脑外的其他上皮细胞中的表达尚不清楚。它是一种跨膜蛋白，在哺乳动物眼睛中高度集中于视网膜外限制膜的顶端。因此，它对粘附体连接的完整性和视网膜细胞的顶基极性所必需的皮质肌动蛋白细胞骨架至关重要。模式图（Credit: Cell）Crb1缺乏小鼠的特点是不同的分散视网膜病变，与外限制膜的破坏和进行性光感受器丧失有关。迄今为止，这些异常被认为是由于细胞极化缺陷和光感受器的细胞-细胞粘附缺陷以及Muller胶质细胞的破坏。由于患者中CRB1突变引起的视网膜表型在外观和视网膜病变的时空分布方面也具有高度的可变性，因此人们假设额外的遗传和环境因素会影响CRB1相关视网膜变性的表达。自然发生的视网膜变性8 (rd8)突变小鼠(Crb1rd8/rd8小鼠，以下简称rd8小鼠)携带一个移帧突变，在Crb1基因中引入一个过早停止密码子，导致Crb1蛋白降解。由于Rd8小鼠表现出与Crb1敲除小鼠(Crb1-/-)相似的视网膜变性表型，它们已被广泛用作Crb1相关视网膜变性的模型。该研究发现CRB1在视网膜色素上皮(RPE)和肠道中均有表达。Crb1突变破坏了视网膜RPE细胞之间和下胃肠道肠细胞之间细胞连接的形成，这与Rd8小鼠变性视网膜中的多种病变内细菌有关。研究证明，眼睛和结肠屏障功能缺陷导致肠道细菌易位和视网膜炎症，而通过无菌(GF)衍生物去除细菌、广谱抗生素全身治疗或在下消化道重新引入功能性Crb1表达成功地预防了眼部疾病的发生和进展。因此，该研究表明，Crb1相关的视网膜变性依赖于肠道细菌的易位，并表明抗菌药物有可能改善这种毁灭性的致盲疾病。原文链接https://www.cell.com/cell/abstract/S0092-8674(24)00108-9责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

临床研究

2024-01-07

·生物谷

想聪明多运动！斯坦福大学Nature发文：运动对大脑有保护作用，“换血”可升级抗炎能力，对神经发生和记忆大有裨益

生命不息，运动不止，运动是健康的基石。钟南山院士曾表示：“锻炼就像吃饭一样，是生活的一部分，我们要建立一种观念，就是要一辈子运动，这样才能有好的生活质量，最大的成功就是健康地活着”。运动的好处数不胜数，坚持运动，不仅可以预防心血管疾病、改善新陈代谢、强身健体等，可能还会让你比同龄人看起来更年轻，拥有更健康的心态！除此之外，运动对于认知衰老和神经退行性变的有益作用也被广泛认可，但介导这些效应的因素和机制尚不明确。2021年12月，斯坦福大学医学院神经病学与神经科学系Tony Wyss-Coray研究团队在Nature杂志发表了一篇题为“Exercise plasma boosts memory and dampens brain inflammation via clusterin”的研究论文[1]，运动小鼠血浆中存在可转移的“抗炎因子”，靶向脑血管系统并有益于大脑，减少非运动小鼠和实验诱导的神经炎症小鼠的海马炎症，这种作用与补体和凝血途径的簇蛋白（CLU）有关，进一步肯定了体育锻炼在认知方面的益处。https://doi.org/10.1038/s41586-021-04183-x首先，基于运动对海马体的有益影响，研究者将运动小鼠的血浆（RP）和未运动小鼠的对照血浆（CP）分别输入到不运动组小鼠体内，观察是否会出现与跑步后类似的效果。结果发现，28天的跑步足以对小鼠海马体产生良好效果，与CP受体小鼠相比，RP受体小鼠的增殖细胞总数、DCX+神经母细胞和存活细胞显著增加，并且值得注意的是，这些结果与上述跑步的直接影响非常相似。与此同时，与CP受体小鼠相比，RP受体小鼠诱导下存活的神经干和祖细胞（NSPCs）增加了一倍，然而，RP并没有显著增加存活的成熟神经元数量，提示运动小鼠的血浆中存在某种成分有可能会改善认知能力。图：RP诱导神经可塑性（来源：文献[1]）并且，进一步的研究发现，运动小鼠的血浆RP可增加小鼠的情境学习和记忆能力，但不影响它们对听觉线索的反应和在明暗场所的活动焦虑水平。随后，为了探究以上影响的分子基础，研究者使用RNA测序技术分析了接受CP或RP注射治疗的小鼠海马转录组，观察到1952个显著差异表达基因（DEGs），其中61%在RP处理后下调，39%在RP处理后上调。与细胞迁移（tn4）、粘附（Igsf5）、上皮细胞分化和增殖（Ehf）相关的基因下调，而与海马学习和记忆（Foxo6）以及免疫系统和可塑性（Fam19a2）相关的基因上调。脂多糖（LPS）是革兰氏阴性菌外膜的主要成分，外周给药可以通过诱导脑血管和中枢神经炎症来模拟与神经退行性疾病相关的神经炎症，接下来，研究者测试了RP输注是否可以减少全身接种LPS的小鼠急性诱导的神经炎症。结果显示，LPS接种导致海马区出现4936个基因差异表达，令人振奋的是，RP治疗逆转了大量这些基因的表达，提示RP可以有效拮抗海马对LPS的神经炎症反应。图：RP对抗LPS诱导的神经炎症（来源：文献[1]）紧接着，研究者探究了跑步对血浆蛋白质组的影响。使用质谱法分析实验组和对照组小鼠的蛋白质组，鉴定出了235种独特的蛋白质，其中，在跑步小鼠的血浆中，有23种蛋白质下调，26种蛋白质上调。生物途径分析指出，补体系统和内皮细胞分化的替代途径被激活，值得注意的是，补体和凝血途径的蛋白质占显著改变蛋白的26%。另外，蛋白质组学分析还显示，CLU、补体因子H（FH）、补体1抑制剂（C1INH）、以及形成膜攻击复合物的末端途径的C8组分的C8 α链和γ链呈现一致增加的趋势。为了鉴定RP的抗炎成分，研究者对RP中四个最大差异表达蛋白（CLU、FH、PEDF、LIFR）进行了免疫缺失操作。其中，CLU具有抗炎作用，与AD有遗传联系，在心脏病中有有益作用；FH具有调节补体和凝血级联的双重作用；糖蛋白色素上皮衍生因子（PEDF）和白血病抑制因子受体（LIFR）也具有强大的抗炎功能。将小鼠全身注射LPS，然后用完整RP（IgG对照抗体）或缺乏CLU、FH、PEDF或LIFR的RP进行处理，8 h后用qPCR分析小鼠海马免疫和炎症基因的表达。结果发现，CLU的缺失在很大程度上消除了RP的抗炎特性，而FH、PEDF或LIFR的缺失几乎没有影响。为了确定CLU对慢性神经炎症模型的影响，研究者分析了应用rCLU或生理盐水治疗8小时的APP小鼠（表现出晚期疾病表型，包括广泛的淀粉样蛋白沉积和小胶质细胞增生，神经元和突触变性以及功能损伤）海马BECs的转录组。观察结果表明，在慢性和急性神经炎症模型中，外周rCLU逆转了APP转基因小鼠BECs中许多异常表达的基因，诱导BECs中干扰素和细胞因子信号通路的一致下调，支持该蛋白的海马抗炎作用。图：CLU减少海马炎症（来源：文献[1]）并且，为了确定在人类身上是否有相同效果，研究者选取了20名患有遗忘性轻度认知障碍的退伍军人，对其进行6个月的体育锻炼干预，使用蛋白质组学平台测量了干预前后的13种补体/凝血蛋白中的8种，包括在小鼠中鉴定的CLU。与小鼠实验结果一致，运动患者CLU显著升高，FX显著降低，补体因子3、凝血因子II、uPA和纤溶酶原降低，广泛反映了运动中的补体和凝血级联反应。综上所述，运动小鼠的血浆可以改善认知功能，并且运动对神经干细胞活性有激活作用，其内在机制可能与通过减少炎症，进而减轻对成人神经发生和认知的潜在负面影响有关。总的来说，该研究为运动有益于大脑的机制提供了新的见解，为开发基于运动诱导的具有减少神经炎症和改善认知功能的蛋白质疗法提供了新的途径。话不多说，一起运动起来吧！参考文献：[1] De Miguel, Z., Khoury, N., Betley, M.J. et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 600, 494–499 (2021).撰文 | 青叶编辑 | 小白精彩推荐：1、仅限男性！BMJ：「单身太久」或「分手频繁」容易引发高水平炎症风险2、低碳水减肥有讲究！JAMA子刊：哈佛大学研究发现这种低碳水化合物饮食未必能减肥，甚至可能让你胖得更快3、久坐伤身不用怕！《英国运动医学杂志》发现每天只需这样运动22分钟即可抵消久坐带来的死亡风险4、如何做到“吃瘦不冲突”？多项研究显示：间歇性能量限制/禁食不仅能够有效减肥，会显著改变肠道菌群和大脑活动5、打破减肥谣言！Cell 子刊：晚上多吃并不一定会变胖，但早餐吃的好饱腹感更强，减肥更容易！本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

2023-08-29

·Science Daily

Enhancing cancer therapy using functionalized photosynthetic bacteria

Selective targeting of cancerous cells poses major clinical challenges during cancer therapy. However, this limitation can be overcome by using bioengineered bacteria with highly optimized chemical modifications. A recent study demonstrates the use of chemically modified purple photosynthetic bacteria for the successful detection and elimination of colon cancer cells in a mouse model. The study also sheds light on the underlying mechanism of action. Targeting malignant tumors with high precision is challenging for biomedical researchers. However, this scenario is likely to witness a paradigm shift in the near future, through the use of specially engineered bacteria, that can eliminate malignant cells efficiently. Using bacteria to target cancer cells, or bacterial therapy, can be further enhanced through genetic engineering and nanotechnology. However, its efficacy may be hindered due to technical constraints and the potential development of antibiotic resistance. Hence, it is crucial to achieve the moderate yet effective chemical modification of bacteria for improved biocompatibility and functionality, such that their medical abilities are not compromised. Recently, certain types of purple photosynthetic bacteria (PPSB) have come into limelight for their potential to address the challenges of bacterial therapy. Exploring this further, a study published online on 14 August, 2023 in Nano Today reports the use of chemically modified PPSB for detecting and eliminating hard-to-eradicate cancerous cells in a mouse model. The study, led by Associate Professor Eijiro Miyako from the Japan Advanced Institute of Science and Technology (JAIST), selected Rhodopseudomonas palustris (RP) as the optimal bacterium for conducting the studies. "RP demonstrated excellent properties, such as near-infrared (NIR) fluorescence, photothermal conversion, and low cytotoxicity. It absorbs NIR light and produces free radicals -- a property that can be utilized to kill cancer cells," explainsProf. Miyako. In an attempt to improve the therapeutic efficacy of the isolated strain, the team sought chemical modifications to alter the bacterial membranes. First, they performed membrane PEGylation, or the attachment of polyethylene glycol derivatives to the bacterial cell walls. Prior research indicates that bacterial PEGylation helps in evading host immune response and converts light energy into heat, which can then be utilized to selectively eliminate cancerous cells. The initial results were encouraging. For instance, coating the RP membrane surface with a "Biocompatible Anchor for Membrane (BAM)" did not adversely affect RP cell viability for at least a week. Moreover, the BAM-functionalized RPs were not eliminated via phagocytosis by macrophages -- cells that play a key role in the immune system's defensive actions against bacterial invasions. Next, the researchers attached a fluorescent "Alexa488-BSA" conjugate to the BAM-functionalized RPs, thus creating a bacterial complex with a trackable fluorescent marker. This conjugate was subsequently replaced with a "PD-L1" antibody. Prior studies have shown that cancer cells express a protein called "Programmed Cell Death Ligand 1 (PD-L1)" on their surface. PD-L1 can smoothly turn off the host defense system by binding to PD-1 receptors. This allows the cancer cells to evade immune detection and elimination. Anti-PD-L1 antibodies block this interaction, thus preventing cancer cells from bypassing immune-system-mediated destruction. As expected, both anti-PD-L1-BAM-RP and RP, inhibited tumor growth in a murine model of colon cancer. However, anti-PD-L1-BAM-RP, BAM-RP, and RP, when excited with a laser, showed an especially dramatic anticancer effect. In fact, solid tumors vanished completely following the laser irradiation of anti-PD-L1-BAM-RP, BAM-RP, or RP that were injected into tumor-bearing mice. Further, on assessing photothermal conversion properties, both anti-PD-L1-BAM-RP and natural RP exhibited strong photothermal conversion due to the presence of light-driven bacteriochlorophyll (BChl) molecules. Among the various bioconjugates, anti-PD-L1-BAM-RP showed the highest efficacy in the initial stage of the treatment. Moreover, it was not toxic to surrounding healthy cells or to the murine host. Subsequent experiments revealed the underlying mechanism of colon tumor annihilation in the mouse model. "Our findings revealed that light-driven functional bacteria demonstrated effective optical and immunological functions in the murine model of colon cancer. Moreover, the NIR fluorescence of the engineered bacterial complexes was used to locate tumors, effectively paving the way for future clinical translation," says Prof. Miyako. He further adds, "We believe that this bacterial technology could be available for clinical trials in 10 years and have positive implications for cancer diagnosis and therapy." Here's hoping that bacterial therapy helps researchers, oncologists, and patients with cancer with much needed relief.