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NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α

  • Hao ZhouEmail author
  • Jin Wang
  • Pingjun Zhu
  • Hong Zhu
  • Sam Toan
  • Shunying Hu
  • Jun RenEmail author
  • Yundai ChenEmail author
Original Contribution

Abstract

Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.

Keywords

Cardiac microvascular IR injury NR4A1 CK2α Mff FUNDC1 Mitochondrial fission Mitophagy 

Notes

Author contributions

HZ is involved in conception and design, performance of experiments, data analysis and interpretation, and manuscript writing. HZ, JW, and PJZ are involved in the development of methodology. HZ and JR are involved in the data acquisition. SYH and PJZ are involved in data analysis and interpretation. HZ and YDC are involved in study supervision and final approval of the manuscript.

Funding

This study was supported by Grants from the National Natural Science Foundation of China (no. 81770237). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

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

Supplementary material

395_2018_682_MOESM1_ESM.docx (2.2 mb)
Supplementary material 1 (DOCX 2289 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of CardiologyPLA General HospitalBeijingChina
  2. 2.Center for Cardiovascular Research and Alternative MedicineUniversity of Wyoming College of Health SciencesLaramieUSA
  3. 3.Department of Chemical and Environmental EngineeringUniversity of California, RiversideRiversideUSA

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