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NR4A1 Aggravates Myocardial Ischaemia–Reperfusion Injury by Inhibiting OPA1-Mediated Mitochondrial Fusion

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Abstract

Mitochondrial fusion is an important process that protects the myocardium. However, mitochondrial fusion is often inhibited in myocardial ischaemia–reperfusion injury (IR). The upstream mechanism of this effect is unclear. Nuclear receptor subfamily 4 group A member 1 (NR4A1) can aggravate myocardial IR and increase the level of oxidative stress, thereby affecting mitochondrial function and morphology. Inhibiting NR4A1 can improve oxidative stress levels and mitochondrial function and morphology, thereby reducing IR. Downregulating NR4A1 increases the expression level of the mitochondrial fusion-related protein optic atrophy 1 (OPA1), which is associated with these benefits. Inhibiting OPA1 expression with MYLS22 abrogates the effects of NR4A1 downregulation on IR. Furthermore, NR4A1 disrupts mitochondrial dynamics and activates the STING and NF-κB pathways. Insufficient mitochondrial fusion and increased apoptosis and inflammatory reactions worsen irreversible damage to cardiomyocytes. In conclusion, NR4A1 can exacerbate IR by inhibiting OPA1, causing mitochondrial damage.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

NR4A1:

Nuclear receptor subfamily 4 group A member 1

OPA1:

Optic atrophy 1

Mfn2:

Mitofusin 2

ROS:

Reactive oxygen species

MPP:

Mitochondrial membrane potential

mPTP:

Mitochondrial permeability transition pore

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Funding

This study was financially supported by grants from the National Natural Science Foundation of China (No. 81870178). 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. Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, China

    Muding Li

  2. School of Medicine, Nankai University, Tianjin, China

    Yingyun Hu

  3. Department of Cardiology, Chinese PLA General Hospital, Beijing, China

    Hao Zhou & Yundai Chen

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  1. Muding Li
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Correspondence to Yundai Chen.

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Li, M., Hu, Y., Zhou, H. et al. NR4A1 Aggravates Myocardial Ischaemia–Reperfusion Injury by Inhibiting OPA1-Mediated Mitochondrial Fusion. J. of Cardiovasc. Trans. Res. 16, 1050–1063 (2023). https://doi.org/10.1007/s12265-023-10396-4

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