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

Hao Zhou, Jin Wang, Pingjun Zhu, Hong Zhu, Sam Q Toan, Shunying Hu, Jun Ren, Yundai Chen

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish (US)
Article number23
JournalBasic Research in Cardiology
Volume113
Issue number4
DOIs
StatePublished - Jul 1 2018

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Mitochondrial Degradation
Mitochondrial Dynamics
Caseins
Reperfusion Injury
Apoptosis
Mitochondria
Protein-Serine-Threonine Kinases
Microvessels
Knockout Mice
Reperfusion
Homeostasis
Ischemia
Phosphorylation
Wounds and Injuries

Keywords

  • CK2α
  • Cardiac microvascular IR injury
  • FUNDC1
  • Mff
  • Mitochondrial fission
  • Mitophagy
  • NR4A1

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. / Zhou, Hao; Wang, Jin; Zhu, Pingjun; Zhu, Hong; Toan, Sam Q; Hu, Shunying; Ren, Jun; Chen, Yundai.

In: Basic Research in Cardiology, Vol. 113, No. 4, 23, 01.07.2018.

Research output: Contribution to journalArticle

Zhou, Hao ; Wang, Jin ; Zhu, Pingjun ; Zhu, Hong ; Toan, Sam Q ; Hu, Shunying ; Ren, Jun ; Chen, Yundai. / NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. In: Basic Research in Cardiology. 2018 ; Vol. 113, No. 4.
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