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The Journal of Physiological Sciences

, Volume 69, Issue 1, pp 113–127 | Cite as

Mst1 promotes cardiac ischemia–reperfusion injury by inhibiting the ERK-CREB pathway and repressing FUNDC1-mediated mitophagy

  • Wancheng Yu
  • Mei Xu
  • Tao Zhang
  • Qian Zhang
  • Chengwei ZouEmail author
Original Paper

Abstract

Cardiac ischemia–reperfusion (I/R) injury results mainly from mitochondrial dysfunction and cardiomyocyte death. Mitophagy sustains mitochondrial function and exerts a pro-survival effect on the reperfused heart tissue. Mammalian STE20-like kinase 1 (Mst1) regulates chronic cardiac metabolic damage and autophagic activity, but its role in acute cardiac I/R injury, especially its effect on mitophagy, is unknown. The aim of this study is to explore whether Mst1 is involved in reperfusion-mediated cardiomyocyte death via modulation of FUN14 domain containing 1 (FUNDC1)-related mitophagy. Our data indicated that Mst1 was markedly increased in reperfused hearts. However, genetic ablation of Mst1 in Mst1-knockout (Mst1-KO) mice significantly reduced the expansion of the cardiac infarction area, maintained myocardial function and abolished I/R-mediated cardiomyocyte death. At the molecular level, upregulation of Mst1 promoted ROS production, reduced mitochondrial membrane potential, facilitated the leakage of mitochondrial pro-apoptotic factors into the nucleus, and activated the caspase-9-related apoptotic pathway in reperfused cardiomyocytes. Mechanistically, Mst1 activation repressed FUNDC1 expression and consequently inhibited mitophagy. However, deletion of Mst1 was able to reverse FUNDC1 expression and thus re-activate protective mitophagy, effectively sustaining mitochondrial homeostasis and blocking mitochondrial apoptosis in reperfused cardiomyocytes. Finally, we demonstrated that Mst1 regulated FUNDC1 expression via the MAPK/ERK-CREB pathway. Inhibition of the MAPK/ERK-CREB pathway prevented FUNDC1 activation caused by Mst1 deletion. Altogether, our data confirm that Mst1 deficiency sends a pro-survival signal for the reperfused heart by reversing FUNDC1-related mitophagy and thus reducing cardiomyocyte mitochondrial apoptosis, which identifies Mst1 as a novel regulator for cardiac reperfusion injury via modulation of mitochondrial homeostasis.

Keywords

Cardiac I/R injury Mitochondrial apoptosis Mst1 FUNDC1 ERK-CREB signaling pathway 

Notes

Author contributions

WCY, MX, and TZ conceived the research; QZ and CWZ performed the experiments; all authors participated in discussing and revising the manuscript.

Funding

This study was supported by the Natural Science Foundation of Shandong Province of China (No. ZR2013HM056), Shandong Province Science and Technology Development Plan (2014GH218016).

Compliance with ethical standards

Conflict of interest statement

The authors have declared that they have no conflicts of interest.

Ethics approval and consent to participate

The animal study was performed in accordance with the Declaration of Helsinki. All experimental protocols were approved by the Ethics Committee of the Department of Cardiac Surgery, Provincial Hospital Affiliated to Shandong University. The ethics reference number is SDQL33SKT1.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

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Copyright information

© The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Wancheng Yu
    • 1
  • Mei Xu
    • 2
  • Tao Zhang
    • 1
  • Qian Zhang
    • 1
  • Chengwei Zou
    • 1
    Email author
  1. 1.Department of Cardiovascular SurgeryShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
  2. 2.Department of GeriatricsShandong University Qilu HospitalJinanChina

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