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NRF1 coordinates mitochondrial adaptations to dampen intracellular ROS and inflammatory responses during ischemia

Jiakun Li1,2, Jiawei Yan3, Guowei Tu4

  • 1Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.

Cell Death Discovery
|May 15, 2025
PubMed

Insights

Nuclear Factor Erythroid 2 Like 1 (NRF1) in macrophages mitigates ischemia reperfusion injury (IRI) by controlling mitochondrial function and reducing oxidative stress. Its absence exacerbates kidney injury and inflammation during IRI.

Area of Science:

  • Immunology
  • Cellular Biology
  • Physiology

Background:

  • Ischemia reperfusion injury (IRI) involves oxidative stress and inflammation, with macrophages playing a key role.
  • The precise mechanisms by which reactive oxygen species (ROS) influence macrophage responses in IRI are not fully understood.

Purpose of the Study:

  • To investigate the role of ROS and macrophage adaptations in IRI.
  • To identify key regulators of mitochondrial homeostasis and inflammatory responses in IRI.

Main Methods:

  • Analysis of macrophage mitochondrial dynamics (fission, fusion) and ubiquitin proteasome system (UPS) flux during reoxygenation.
  • Investigating the induction and function of transcription factor Nuclear Factor Erythroid 2 Like 1 (NRF1) in response to ROS.
  • Utilizing a mouse model of IRI to assess the impact of myeloid NRF1 deficiency on kidney injury and inflammation.

Main Results:

  • Macrophages exhibit mitochondrial fission and increased UPS flux during reoxygenation in IRI.
  • ROS rapidly induce NRF1, which upregulates UPS and mitophagy pathways, promoting mitochondrial fusion/fission dynamics and reducing ROS.
  • Absence of myeloid NRF1 in mice leads to elevated ROS, heightened inflammation, and exacerbated kidney injury in an IRI model.

Conclusions:

  • Macrophage NRF1 is a critical regulator of mitochondrial homeostasis and antioxidant defense during IRI.
  • NRF1 activation in macrophages alleviates oxidative stress and dampens inflammatory responses, thereby protecting against IRI.
  • Targeting macrophage NRF1 may offer a therapeutic strategy for mitigating IRI and associated organ damage.

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