Last update 19 Sep 2024

PGAM5

Last update 19 Sep 2024

Basic Info

Synonyms

Bcl-XL-binding protein v68, BXLBv68, MGC5352

+ [4]

Introduction

Displays phosphatase activity for serine/threonine residues, and, dephosphorylates and activates MAP3K5 kinase. Has apparently no phosphoglycerate mutase activity. May be regulator of mitochondrial dynamics. Substrate for a KEAP1-dependent ubiquitin ligase complex. Contributes to the repression of NFE2L2-dependent gene expression. Acts as a central mediator for programmed necrosis induced by TNF, by reactive oxygen species and by calcium ionophore.

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

233

Literatures (Medical) associated with PGAM5

01 Dec 2024·Computational and Structural Biotechnology Journal

Identification and validation of protein biomarkers for predicting gastrointestinal stromal tumor recurrence

Article

Author: Li, Jie ; He, Yixuan ; Kang, Weiming ; Sun, Juan ; Ye, Xin

We conducted a proteomic analysis using mass spectrometry to identify and validate protein biomarkers for accurately predicting recurrence risk in gastrointestinal stromal tumors (GIST) patients, focusing on differentially expressed proteins in metastatic versus primary GIST tissues. We selected five biomarkers-GPX4, RBM4, TPM3, PFKFB2, and PGAM5-and validated their expressions in primary tumors of recurrent and non-recurrent GIST patients via immunohistochemistry. Our analysis of the association between these biomarkers with recurrence-free survival (RFS) and overall survival (OS), along with their interrelationships, revealed that immunohistochemistry confirmed significantly higher expressions of these biomarkers in primary GIST tissues of recurrent patients. Kaplan-Meier survival analysis showed that high expressions of GPX4, RBM4, TPM3, PFKFB2, and PGAM5 correlated with lower RFS, and GPX4 and RBM4 with lower OS. All biomarker pairs showed positive associations, with high expressions correlating with increased recurrence rates, and GPX4 and RBM4 with higher mortality rates. In conclusion, the biomarkers GPX4, RBM4, TPM3, PFKFB2, and PGAM5 are clinically relevant for predicting GIST recurrence, with their high expressions in primary tumors linked to poorer RFS and OS. They serve as potential prognostic indicators, enabling early treatment and improved outcomes. The observed interrelationships among these biomarkers further validate their accuracy in predicting GIST recurrence.

01 Dec 2024·Brain Research

The KEAP1/PGAM5/AIFM1-Mediated oxeiptosis pathway in Alzheimer’s disease

Article

BACKGROUNDAlzheimer's Disease (AD) is a neurodegenerative disease with mitochondrial dysfunction and oxidative stress. Oxeiptosis is a cell death pathway sensitive to reactive oxygen species (ROS). This study investigates the role of oxeiptosis pathway and mitochondrial damage in AD.METHODSAn AD model was developed in C57BL/6 mice by injecting Aβ_1-42 oligomers into the brain. Cognitive function was tested using the Morris water maze. Exposure of HT22 mouse hippocampal neurons to H₂O₂ induces oxidative stress. Protein levels of KEAP1, PGAM5 and AIFM1 were analyzed by western blot, and mitochondrial damage was observed with electron microscopy. Cell survival rates were using the CCK8 assay and flow cytometry after knocking down KEAP1, PGAM5 and AIFM1.RESULTSThe protein concentrations of KEAP1, PGAM5 and AIFM1 were found to be elevated in the hippocampal tissues of AD mice compared to control group, accompanied by mitochondrial damage in the hippocampal neurons of the AD group. Similarly, in the HT22 oxidative stress model, there was an increase in the protein levels of KEAP1, PGAM5 and AIFM1, along with observed mitochondrial damage. Following individual and combined knockdown of KEAP1, PGAM5 and AIFM1, cell survival rates under oxidative stress conditions were higher compared to H₂O₂ group, with no significant difference in cell survival rates among the knockdown groups.CONCLUSIONThis research underscores the critical role of the KEAP1/PGAM5/AIFM1-mediated oxeiptosis pathway in neuronal cell death, offering insights into potential therapeutic targets for mitigating neurodegeneration in AD.

01 Oct 2024·Metabolism

RIPK3 causes mitochondrial dysfunction and albuminuria in diabetic podocytopathy through PGAM5-Drp1 signaling

Article

Author: Lee, Ji-Hye ; Lee, Eun Young ; Moon, Jong-Seok ; Gil, Hyo-Wook ; Lee, Donghyeong ; Oh, Joon Cheol ; Chung, Choon Hee ; Lee, Seong Woo ; Kim, Sang Soo ; Park, Samel ; Son, Seung Seob ; Kim, So-Young ; Park, Mi Ju ; Park, Jihwan ; Choi, Min Sun ; Yi, Jawoon ; Cho, Nam-Jun ; Kang, Jeong Suk ; Yang, Seung-Hoon ; Lee, Eun Soo ; Lee, Jeong Geon

BACKGROUNDReceptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD.METHODSWe analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in Ripk3 knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3.RESULTSRIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (p = 0.002) and non-albuminuric diabetic patients (p = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05-4.98]) and incident chronic kidney disease (HR 4.08 [1.10-15.13]). Ripk3 knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of Ripk3 knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1.CONCLUSIONSThe study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.

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