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Last update 08 May 2025

PGAM5

Last update 08 May 2025

Basic Info

Synonyms

Bcl-XL-binding protein v68, BXLBv68, MGC5352

+ [4]

Introduction

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).

Drugs associated with PGAM5

LFHP-1c

Target

PGAM5

Mechanism

PGAM5 inhibitors

Active Org.

Guangdong Longfu Medicine Co. Ltd.

Originator Org.

Guangdong Longfu Medicine Co. Ltd.

Active Indication

Ischemic stroke

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PGAM5

100 Translational Medicine associated with PGAM5

0 Patents (Medical) associated with PGAM5

271

Literatures (Medical) associated with PGAM5

01 Jun 2025·Cellular Signalling

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

Article

Author: 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.

04 May 2025·International Journal of Radiation Biology

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

Article

Author: 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.

01 Apr 2025·Archives of Gerontology and Geriatrics

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

Article

Author: 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.

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