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ROS-induced cytosolic release of mitochondrial PGAM5 accelerates colorectal cancer progression via MST3-mediated YAP activation

ABSTRACT: Aberrant mtROS release in response to mitochondrial stress are considered to be a major novel feature of neoplastic transformation. However, the molecular mechanisms by which mtROS contribute to CRC development have not been fully elucidated. In this study, we showed that upon sensing the mtROS signal, the mitochondrially localized phosphatase PGAM5 undergoes cleavage in the mitochondrial transmembrane domain, and then the Cleaved PGAM5 is released into the cytoplasm. Subsequently, Cleaved PGAM5 binds to the kinase MST3 in the cytoplasm to promote MST3 dephosphorylation, resulting in a decrease in MST3 activity. Importantly, MST3 inactivation failed to regulate YAP phosphorylation, leading to YAP translocation into the nucleus, consequently promoting CRC proliferation and metastasis. Collectively, our findings identified the PGAM5-MST3-YAP axis as an important molecular mechanism through which mtROS promotes CRC development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249865 | GEO | 2024/11/05

REPOSITORIES: GEO

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ROS-induced cytosolic release of PGAM5 accelerates cancer progression via MST3-YAP axis

Project description:Aberrant mtROS release in response to mitochondrial stress are considered to be a major novel feature of neoplastic transformation. However, the molecular mechanisms by which mtROS contribute to CRC development have not been fully elucidated. In this study, we showed that upon sensing the mtROS signal, the mitochondrially localized phosphatase PGAM5 undergoes cleavage in the mitochondrial transmembrane domain, and then the Cleaved PGAM5 is released into the cytoplasm. Subsequently, Cleaved PGAM5 binds to the kinase MST3 in the cytoplasm to promote MST3 dephosphorylation, resulting in a decrease in MST3 activity. Importantly, MST3 inactivation failed to regulate YAP phosphorylation, leading to YAP translocation into the nucleus, consequently promoting CRC proliferation and metastasis. Collectively, our findings identified the PGAM5-MST3-YAP axis as an important molecular mechanism through which mtROS promotes CRC development.

2024-11-05 | GSE248431 | GEO

Mitochondrial PGAM5−Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses

Project description:Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-kB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling might be a link between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.

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ROS-induced cytosolic release of mitochondrial PGAM5 accelerates colorectal cancer progression via MST3-mediated YAP activation

Project description:ROS-induced cytosolic release of mitochondrial PGAM5 accelerates colorectal cancer progression via MST3-mediated YAP activation

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ROS-induced cytosolic release of PGAM5 accelerates cancer progression via MST3-YAP axis

Project description:ROS-induced cytosolic release of PGAM5 accelerates cancer progression via MST3-YAP axis

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Gene expression profiles of PGAM5-knockout brown adipose tissue

Project description:PGAM5 is a mitochondria-localized protein phosphatase. To analyze the effect on gene expression profiles by PGAM5 in iBAT, RNA-seq analysis was performed.

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PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in Drosophila

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Project description:Deubiquitinating enzymes have gained more and more attention in the field of pathological cardiac hypertrophy. In this study, we explored the role of a deubiquitinase, OTUD1, in the transverse aortic constriction (TAC) induced cardiac hypertrophy. We found the upregulation of OTUD1 in heart tissues of TAC mice. OTUD1 overexpression promoted cardiac hypertrophy, cardiac fibrosis and apoptosis. Conversely, OTUD1 depletion alleviated these pathological changes both in vivo and in vitro. Mechanistically, ASK1 was identified as one substrate of OTUD1 using co-immunoprecipitation followed with LC-MS/MS. Interestingly, OTUD1 didn’t deubiquitinate ASK1, but increased the phosphorylation level of ASK1 during the process of cardiac hypertrophy. We found that PGAM5, the upper stream regulator of ASK1, was stabilized by OTUD1 in a K63 ubiquitin chain dependent way, which reminded us OTUD1 increased the phosphorylation level of ASK1 by deubiquitinating PGAM5. This study identified the OTUD1-ASK1 axis as a potential therapeutic target for pathological cardiac hypertrophy.

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