Phosphoglycerate mutase 1-mediated dephosphorylation and degradation of Dusp1 disrupt mitochondrial quality control and exacerbate endotoxemia-induced myocardial dysfunction

Theranostics. 2024 Nov 4;14(19):7488-7504. doi: 10.7150/thno.102647. eCollection 2024.

Abstract

Rationale: Endotoxemia, caused by lipopolysaccharides, triggers systemic inflammation and myocardial injury by disrupting mitochondrial homeostasis. This study examines the roles of dual specificity phosphatase 1 (Dusp1) and phosphoglycerate mutase family member 1 (Pgam1) in this process. Methods: This study utilized cardiomyocyte-specific Dusp1 knockout (Dusp1Cko ) and transgenic (Dusp1Tg ) mice, alongside Pgam1 knockout (Pgam1Cko ) mice, subjected to LPS-induced endotoxemia. Echocardiography was performed to assess cardiac function. Mitochondrial integrity was evaluated using molecular techniques, including qPCR and Seahorse assays. Additionally, molecular docking studies and Western blot analyses were conducted to explore the interaction between Pgam1 and Dusp1. Results: Using single-cell sequencing and human sample databases, Dusp1 emerged as a novel biomarker for endotoxemia-induced myocardial dysfunction. Experiments with cardiomyocyte-specific Dusp1 knockout (Dusp1Cko ) and Dusp1 transgenic (Dusp1Tg ) mice showed that Dusp1 deficiency worsens, while overexpression improves, heart function during LPS-induced myocardial injury. This effect is mediated by regulating inflammation and cardiomyocyte viability. Molecular analyses revealed that LPS exposure leads to Dusp1 dephosphorylation at Ser364, increasing its degradation. Stabilizing Dusp1 phosphorylation enhances mitochondrial function through mitochondrial quality control (MQC), including dynamics, mitophagy, and biogenesis. Functional studies identified Pgam1 as an upstream phosphatase interacting with Dusp1. Pgam1 ablation reduced LPS-induced cardiomyocyte dysfunction and mitochondrial disorder. Conclusions: Pgam1-mediated dephosphorylation of Dusp1 disrupts mitochondrial quality control, leading to myocardial dysfunction in endotoxemia. Targeting the Pgam1-Dusp1 axis represents a promising therapeutic strategy for improving cardiac outcomes in patients with endotoxemia.

Keywords: Dusp1; LPS; Pgam1; endotoxemia; mitochondrial quality control.

MeSH terms

  • Animals
  • Cardiomyopathies / etiology
  • Cardiomyopathies / metabolism
  • Dual Specificity Phosphatase 1* / genetics
  • Dual Specificity Phosphatase 1* / metabolism
  • Endotoxemia* / metabolism
  • Humans
  • Lipopolysaccharides*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Molecular Docking Simulation
  • Myocytes, Cardiac* / metabolism
  • Phosphoglycerate Mutase* / genetics
  • Phosphoglycerate Mutase* / metabolism
  • Phosphorylation

Substances

  • Dual Specificity Phosphatase 1
  • Phosphoglycerate Mutase
  • Dusp1 protein, mouse
  • Lipopolysaccharides
  • DUSP1 protein, human
  • phosphoglycerate mutase 1, human