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

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.