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更新于：2025-05-07

PGAM5

更新于：2025-05-07

基本信息

别名

Bcl-XL-binding protein v68、BXLBv68、MGC5352

+ [4]

简介

Mitochondrial serine/threonine phosphatase that dephosphorylates various substrates and thus plays a role in different biological processes including cellular senescence or mitophagy (PubMed:24746696, PubMed:32439975). Modulates cellular senescence by regulating mitochondrial dynamics. Mechanistically, participates in mitochondrial fission through dephosphorylating DNM1L/DRP1 (PubMed:32439975). Additionally, dephosphorylates MFN2 in a stress-sensitive manner and consequently protects it from ubiquitination and degradation to promote mitochondrial network formation (PubMed:37498743). Regulates mitophagy independent of PARKIN by interacting with and dephosphorylating FUNDC1, which interacts with LC3 (PubMed:24746696). Regulates anti-oxidative response by forming a tertiary complex with KEAP1 and NRF2 (PubMed:18387606). Regulates necroptosis by acting as a RIPK3 target and recruiting the RIPK1-RIPK3-MLKL necrosis 'attack' complex to mitochondria (PubMed:22265414).

关联

项与 PGAM5 相关的药物

LFHP-1c

靶点

PGAM5

作用机制

PGAM5 inhibitors

在研机构

Guangdong Longfu Medicine Co. Ltd.

原研机构

Guangdong Longfu Medicine Co. Ltd.

在研适应症

缺血性卒中

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 PGAM5 相关的临床结果

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100 项与 PGAM5 相关的转化医学

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0 项与 PGAM5 相关的专利（医药）

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271

项与 PGAM5 相关的文献（医药）

2025-06-01·Cellular Signalling

AECII-derived miR-21a-5p exosomes alleviate HALI via targeting and regulating PGAM5-mediated necroptosis

Article

作者: Ren, Yingcong ; Cao, Yunliang ; Yuan, Ping ; Qin, Song ; Huang, Qianxia ; Chen, Miao ; Liu, GuoYue ; Shi, Yuanzhi ; Huang, Ma

Hyperoxic Acute Lung Injury (HALI) is a serious complication of prolonged high-concentration oxygen therapy, primarily leading to Acute Respiratory Distress Syndrome (ARDS), which primarily affects alveolar epithelial cells (AECs). Exosomes (Exos) derived from type II alveolar epithelial cells (AEC IIs) play a crucial role in lung protection through their contained microRNAs (miRNAs). Previous research has established miR-21a-5p as a key player in pulmonary defense mechanisms. In this study, we utilized a C57BL/6 mouse model of HALI established by hyperoxic conditions (FiO₂ > 90 %) to demonstrate a gradual decrease in miR-21a-5p levels concomitant with an increase in PGAM5 levels with prolonged hyperoxia exposure. Exosomal transcriptome sequencing suggested significant downregulation of miR-21a-5p expression in hyperoxia-stimulated AECII exosomes. We employed dual-luciferase reporter assays and Chromatin Isolation by RNA Purification (ChIRP) to confirm the direct interaction between miR-21a-5p and PGAM5. AECII-derived exosomal miR-21a-5p effectively attenuated lung injury and inhibited the expression of proteins associated with PGAM5-mediated necroptosis (RIPK1, RIPK3, p-MLKL). Furthermore, in vitro assays using MLE-12 cells confirmed that AECII-derived exosomal miR-21a-5p intervention reversed the elevated levels of necroptotic apoptotic proteins in hyperoxia-stimulated MLE-12 cells. These findings collectively demonstrate that AECII-derived exosomal miR-21a-5p inhibits necroptosis pathway activity by modulating PGAM5, thereby exerting lung-protective effects. Therefore, exosomal miR-21a-5p may serve as a novel therapeutic target for attenuating HALI via modulation of the PGAM5-mediated necroptotic pathway.

2025-05-04·International Journal of Radiation Biology

Prohibitin2 knockdown decreases glioma malignant phenotypes and radio-resistance by inhibiting mitophagy

Article

作者: Tan, Huiling ; Jiang, Xingning ; Yang, Wei ; Lu, Jingfan ; Xue, Xuefei ; Sun, Ting

PURPOSEProhibitin2 (PHB2), located in inner mitochondrial membrane (IMM), is an important receptor to induce mitophagy. PHB2 was identified as a cancer-promoting factor in most cancers. However, the function of PHB2 in glioma cells remains unclear. This study delved into the impact of PHB2 knockdown on the phenotype, radiosensitivity and mitophagy of glioma cells.METHODSPHB2 expression and its clinical relevance in glioma were investigated by western blot, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and TCGA databases. The malignant phenotypes of glioma cells were analyzed in vitro using cell proliferation, cell cycle, wound healing and transwell assay. The radiosensitivity of glioma cells was detected by colony forming assay. The potential mechanism by which PHB2 regulated mitophagy was investigated by coimmunoprecipitation assay.RESULTSThe expression of PHB2 was significantly upregulated in glioma cells and closely correlated with the malignant degree of glioma. The knockdown of PHB2 inhibited the proliferation, migration and invasion activities of glioma cells. Furthermore, PHB2 knockdown enhanced the radiosensitivity of normoxic and hypoxic glioma cells and suppressed the ionizing radiation-induced mitophagy in glioma cells. Cyanide 3-chlorophenylhydrazone (CCCP), a mitophagy agonist, could reverse the phenotypes and radiosensitivity changes elicited by PHB2 knockdown. Additionally, PHB2 regulated the expression of PGAM5 and PINK1 by directly binding to PARL.CONCLUSIONSOur findings revealed that PHB2 knockdown decreased glioma malignant phenotypes and radio-resistance by inhibiting mitophagy via PARL-PGAM5-PINK1-Parkin pathway. PHB2 is a promising candidate target for the development of new therapeutic strategy to enhance the efficacy of radiotherapy for glioma.

2025-04-01·Archives of Gerontology and Geriatrics

Inhibition of PGAM5 hyperactivation reduces neuronal apoptosis in PC12 cells and experimental vascular dementia rats

Article

作者: Wu, Xuzhou ; Sun, Chunying ; Chen, Canrong ; Yao, Chun ; Qin, Hongling ; Jiang, Minghe ; Li, Fangcun ; Zhang, Ding ; Hu, Yueqiang ; Zhou, Keqing

PURPOSEThe incidence of vascular dementia (VaD), as one of the main types of dementia in old age, has been increasing year by year, and exploring its pathogenesis and seeking practical and effective treatment methods are undoubtedly the key to solving this problem. Phosphoglycerate translocase 5 (PGAM5), as a crossroads of multiple signaling pathways, can lead to mitochondrial fission, which in turn triggers the onset and development of necroptosis, and thus PGAM5 may be a novel target for the prevention and treatment of vascular dementia.METHODSAnimal model of vascular dementia was established by Two-vessel occlusion (2-VO) method, and cellular model of vascular dementia was established by oxygen glucose deprivation (OGD) method. Neuronal damage was detected in vivo and in vitro in different groups using different concentrations of the PGAM5-specific inhibitor LFHP-1c, and necroptosis and mitochondrial dynamics-related factors were determined.RESULTSIn vivo experiments, 10 mg/kg^-1 and 20 mg/kg^-1 LFHP-1c improved cognitive deficits, reduced neuronal edema and vacuoles, increased the number of nissl bodies, and it could modulate the expression of Caspase family and Bcl-2 family related proteins and mRNAs and ameliorate neuronal damage. Simultaneously, in vitro experiments, 5 μM, 10 μM and 20 μM LFHP-1c increased the activity and migration number of model cells, reduced the number of apoptotic cells, ameliorated the excessive accumulation of intracellular reactive oxygen species, inhibited the over-activation of caspase-family and Bcl-2-family related proteins and mRNAs, and improved the mitochondrial dynamics of the fission and fusion states. Moreover, in vivo and in vitro experiments have shown that LFHP-1c can also upregulate the expression level of BDNF, inhibit the expression content of TNF-α and ROS, regulate the expression of proteins and mRNAs related to the RIPK1/RIPK3/MLKL pathway and mitochondrial dynamics, and reduce neuronal apoptosis.CONCLUSIONSInhibition of PGAM5 expression level can reduce neuronal damage caused by chronic cerebral ischemia and hypoxia, which mainly prevents necroptosis by targeting the RIPK1/RIPK3/MLKL signaling pathway and regulates the downstream mitochondrial dynamics homeostasis system to prevent excessive mitochondrial fission, thus improving cognition and exerting cerebroprotective effects.

项与 PGAM5 相关的新闻（医药）

2024-03-03

·今日头条

再次发力！复旦张英梅教授、葛均波院士等合作发文

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：众所周知，炎症小体活化和热噬细胞死亡有助于心血管疾病的发病机制，例如心肌缺血—再灌注（I/R）损伤，但其潜在调节机制仍知之甚少。 2024年2月28日，复旦大学张英梅、葛均波联合中国科学院分子细胞科学卓越创新中心胡荣贵共同在《Cell Discovery》上发表题为“The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis”的研究论文，研究表明E3泛素连接酶MARCH2通过负调控PGAM5/MAVS/NLRP3轴抑制心肌焦亡，保护心肌缺血再灌注损伤。 https://www.nature.com/articles/s41421-023-00622-3 研究背景 01 炎性小体是一种大分子结构，负责感知损伤并引发一系列炎症反应。炎症小体最具特征的传感器是NACHT、LRR和PYD结构域蛋白3 (NLRP3)，它们在无菌炎症反应中被激活。NLRP3炎症小体激活有助于许多炎症性疾病的病理生理学。例如，由损伤相关分子模式（DAMP）激活的 NLRP3 炎症小体参与非酒精性脂肪性肝病的发病机制。此外，发现 NLRP3 和炎性细胞因子 IL-18 和 IL-1β 的表达水平在动脉粥样硬化斑块发展中升高。此外，NLRP3 的敲除（KO）通过消除活性氧（ROS）和线粒体损伤诱发的炎症小体激活来防止高脂肪饮食引起的肥胖和胰岛素抵抗。心肌梗死（MI）仍然是全球残疾和死亡的主要原因之一。及时恢复通过闭塞冠状动脉的血流是心肌梗死患者的最佳操作。然而，这种再灌注可能会激活心肌的级联有害损伤，称为缺血再灌注（I/R）损伤。新出现的证据表明，炎症小体的激活是炎症驱动的心肌 I/R 损伤的一个组成部分。已知抑制 NLRP3 炎症小体激活可限制心肌 I/R 损伤后的梗死面积和心功能障碍。因此，鉴定 NLRP3 炎症小体的内源性调节剂以抑制其激活可能在临床上有益。研究结果 02 我们的研究结果表明，MARCH2 对心肌 I/R 损伤、炎症小体激活和心肌细胞焦亡具有突出的心脏保护作用。MARCH2 在 ICM 患者和 I/R 激发小鼠心脏中上调。MARCH2 消融术加重了 I/R 诱发的心肌损伤，梗死面积、超声心动图参数和心肌细胞力学证明了这一点。我们的进一步分析表明， MARCH2 通过介导其 K48 连接的 polyUb 促进 PGAM5 的降解，以及通过 PGAM5/MAVS/NLRP3 依赖性机制缓解 I/R 损伤后的炎症反应和热沉细胞死亡（图 8j）。特别是，PGAM5-MAVS 缩合物介导 NLRP3 炎症小体的激活，可能充当 PGAM5/MAVS/NLRP3 海绵并促进 GSDMD 和 IL-18 的 caspase-1 依赖性切割。此外，使用 AAV9-cTnT-MARCH2 异位表达 MARCH2 可有效改善 I/R 损伤诱发的心肌损伤。在这种情况下，MARCH2 对 I/R 诱发的心肌损伤有益。 MARCH2 功能在 I/R 损伤中的工作模型。 MARCH2 通过促进 PGAM5 的 K48 连接的 polyUb 与 PGAM5 相互作用并促进其降解，从而抑制 MAVS/NLRP3 炎症小体通路和心肌细胞焦亡的活性。研究结论 03 总之，我们的研究结果不仅确立了 E3 连接酶 MARCH2 作为对抗心肌 I/R 损伤的新型心脏保护分子，而且还确定了一种以前未知的机制，该机制负调控 PGAM5/MAVS/NLRP3 炎症小体信号传导和焦亡，以维持哺乳动物心脏的稳态和正常功能。因此，靶向 MARCH2 可能代表了对抗心肌损伤的新机会。参考资料： https://www.nature.com/articles/s41421-023-00622-3 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 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！点击对应文字查看详情

2024-03-02

·生物探索

Cell Discov | 复旦大学张英梅/葛均波等合作揭示MARCH2对抗心肌缺血再灌注伤害的机制

引言炎症小体激活和焦亡会促进心肌缺血-再灌注(I/R)损伤，但其潜在的调节机制尚不清楚。2024年2月28日，复旦大学张英梅、葛均波及中国科学院分子细胞科学卓越创新中心胡荣贵共同通讯在Cell Discovery（IF 34）在线发表题为“The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis”的研究论文，该研究表明E3泛素连接酶MARCH2通过负调控PGAM5/MAVS/NLRP3轴抑制心肌焦亡，保护心肌缺血再灌注损伤。炎症小体是一种大分子结构，负责感知损伤并引发一系列炎症反应。炎症小体最具特征的传感器是NACHT、LRR和PYD结构域蛋白3 (NLRP3)，它们在无菌炎症反应中被激活。炎症小体传感器NLRP3的激活会募集含有caspase-募集结构域(ASC)和效应蛋白caspase-1的接头凋亡相关斑点样蛋白，通过促进焦亡直接触发严重的组织损伤，并通过IL-18的分泌间接触发。新出现的证据表明，炎症小体的激活是炎症驱动的心肌I/R损伤的一个组成部分。抑制NLRP3炎性小体激活可以限制心肌I/R损伤后的梗死面积和心功能障碍。因此，鉴定内源性NLRP3炎症小体的调节剂以抑制其激活可能对临床有益。I/R损伤中MARCH2功能的工作模型（Credit: Cell Discovery）泛素(Ub)-蛋白酶体系统调节许多细胞过程中的蛋白质降解和稳态。因此，识别关键的泛素化相关调节剂可能减轻心肌I/R损伤。为此，研究人员对心肌I/R损伤小鼠的心脏样本进行了单细胞RNA测序(scRNA-seq)。研究发现E3连接酶膜相关环指蛋白2 (MARCH2)上调，MARCH2是MARCH E3 Ub连接酶亚家族的成员，包括11个成员，主要定位于内质网、核内体、高尔基体、线粒体和质膜。已知MARCH2通过与syntaxin-616相互作用调节核内体和反面高尔基管网结构。之间的囊泡运输以及回收核内体。研究还显示，MARCH2通过促进CFTR的泛素化和降解以及激活PIK3CA-AKT-mTOR通路，负向调节肿瘤细胞的自噬。利用MARCH2 KO和AAV9cTnT-MARCH2转染小鼠模型，该研究表明，MARCH2改善心肌I/R损伤并抑制NLRP3炎症小体的激活。研究发现，MARCH2与磷酸甘油酸突变酶家族成员5 (PGAM5)相互作用，促进其与K48相关的泛素化和降解。PGAM5的泛素非依赖性降解导致PGAM5-线粒体抗病毒信号蛋白(MAVS)相分离凝聚物的抑制和下游NLRP3炎症小体的激活。这些发现证明了MARCH2作为心肌I/R损伤的新治疗靶点的重要作用。原文链接https://www.nature.com/articles/s41421-023-00622-3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

蛋白降解靶向嵌合体