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DUSP1 interacts with and dephosphorylates VCP to improve mitochondrial quality control against endotoxemia-induced myocardial dysfunction

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Abstract

Dual specificity phosphatase 1 (DUSP1) and valosin-containing protein (VCP) have both been reported to regulate mitochondrial homeostasis. However, their impact on mitochondrial quality control (MQC) and myocardial function during LPS-induced endotoxemia remains unclear. We addressed this issue by modeling LPS-induced endotoxemia in DUSP1 transgenic (DUSP1TG) mice and in cultured DUSP1-overexpressing HL-1 cardiomyocytes. Accompanying characteristic structural and functional deficits, cardiac DUSP1 expression was significantly downregulated following endotoxemia induction in wild type mice. In contrast, markedly reduced myocardial inflammation, cardiomyocyte apoptosis, cardiac structural disorder, cardiac injury marker levels, and normalized systolic/diastolic function were observed in DUSP1TG mice. Furthermore, DUSP1 overexpression in HL-1 cells significantly attenuated LPS-mediated mitochondrial dysfunction by preserving MQC, as indicated by normalized mitochondrial dynamics, improved mitophagy, enhanced biogenesis, and attenuated mitochondrial unfolded protein response. Molecular assays showed that VCP was a substrate of DUSP1 and the interaction between DUSP1 and VCP primarily occurred on the mitochondria. Mechanistically, DUSP1 phosphatase domain promoted the physiological DUSP1/VCP interaction which prevented LPS-mediated VCP Ser784 phosphorylation. Accordingly, transfection with a phosphomimetic VCP mutant abolished the protective actions of DUSP1 on MQC and aggravated inflammation, apoptosis, and contractility/relaxation capacity in HL-1 cardiomyocytes. These findings support the involvement of the novel DUSP1/VCP/MQC pathway in the pathogenesis of endotoxemia-caused myocardial dysfunction.

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Data availability

The data supporting the findings of this study are found within the article and the supplementary material. All relevant raw data will be made available from the corresponding author upon reasonable request.

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Funding

This study was supported by grants from the NSFC (Nos. 82270279 and 82200296) and Youth Innovative Talents Training Program of Tianjin First Central Hospital Young Talents.

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  1. Hang Zhu and Jin Wang contributed equally to this article.

Authors and Affiliations

  1. Senior Department of Cardiology, The Sixth Medical Center of People’s Liberation Army General Hospital, Beijing, 100048, China

    Hang Zhu, Shanshan Chen, Ruiying Hu & Hao Zhou

  2. Department of Vascular Medicine, Peking University Shougang Hospital, Beijing, 100144, China

    Jin Wang

  3. Department of Cardiology, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, 300192, People’s Republic of China

    Ting Xin

  4. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Yukun Li

  5. Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi’an, 710038, China

    Mingming Zhang

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  1. Hang Zhu
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Contributions

JW and HZ conceived the original experiments. TX and YL contributed to the manuscript revision. SC and RH, and HZ, carried out all the in vivo experiments and molecular investigation in vitro. HZ and MZ wrote the whole manuscript. HZ, MZ, HZ revised the final version of manuscript. All the authors read the article and approved the submission.

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Correspondence to Mingming Zhang or Hao Zhou.

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Experiments were performed under a project license (Beijing, China) granted by the committee on the Ethics of Chinese PLA General Hospital, in compliance with the Guidelines for the Management and Use of Laboratory Animals.

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Zhu, H., Wang, J., Xin, T. et al. DUSP1 interacts with and dephosphorylates VCP to improve mitochondrial quality control against endotoxemia-induced myocardial dysfunction. Cell. Mol. Life Sci. 80, 213 (2023). https://doi.org/10.1007/s00018-023-04863-z

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