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RETRACTED ARTICLE: NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial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

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This article was retracted on 15 June 2023

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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.

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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.

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Authors and Affiliations

  1. Department of Cardiology, PLA General Hospital, Beijing, China

    Hao Zhou, Jin Wang, Pingjun Zhu, Shunying Hu & Yundai Chen

  2. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA

    Hao Zhou, Hong Zhu & Jun Ren

  3. Department of Chemical and Environmental Engineering, University of California, Riverside, Riverside, CA, 92521, USA

    Sam Toan

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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.

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Correspondence to Hao Zhou, Jun Ren or Yundai Chen.

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Zhou, H., Wang, J., Zhu, P. et al. RETRACTED ARTICLE: NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic Res Cardiol 113, 23 (2018). https://doi.org/10.1007/s00395-018-0682-1

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