Phosphoglycerate mutase 1-mediated dephosphorylation and degradation of Dusp1 disrupt mitochondrial quality control and exacerbate endotoxemia-induced myocardial dysfunction
Rongjun Zou, Wanting Shi, Mingxian Chen, Miao Zhang, Dan Wu, Haixia Li, Hao Zhou, Yukun Li, Weihui Lu, Chao Li, Xiaoping Fan
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 (Dusp1 Cko ) and transgenic (Dusp1 Tg ) mice, alongside Pgam1 knockout (Pgam1 Cko ) 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 (Dusp1 Cko ) and Dusp1 transgenic (Dusp1 Tg ) 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.