NLRX1, NLR family member X1, is a unique pattern recognition molecule of the Nod-like receptor (NLR) family. It localizes to the mitochondrial matrix in resting conditions and is involved in multiple cellular processes. It has been proposed to regulate antiviral immunity, apoptosis, ROS generation, mitochondrial metabolism, and mitophagy [2]. It also negatively regulates type-I interferon, attenuates pro-inflammatory NF-κB signaling, and modulates autophagy, cell death, and proliferation [3].

In studies related to NLRX1, gene knockout models have provided valuable insights. NLRX1-deficient nucleus pulposus (NP) cells showed disordered mitochondrial quality, leading to NP cell senescence and intervertebral disc degeneration (IDD) progression. Conversely, restoration of NLRX1 function could sustain mitochondrial homeostasis, ameliorate NP cell senescence, and rejuvenate intervertebral discs [1]. In macrophages, NLRX1 knockout led to enhanced M2 polarization markers, tubular injury, and fibrosis in a mouse model of chronic obstructive nephropathy, suggesting its role in preventing excessive renal fibrosis [4].

In conclusion, NLRX1 is a multifaceted regulator involved in key cellular processes such as mitochondrial dynamics, mitophagy, and immune-related signaling. Gene knockout mouse models have revealed its significance in diseases like IDD and chronic obstructive nephropathy. Understanding NLRX1 could offer potential therapeutic strategies for these and other related diseases.

References:

1. Song, Yu, Liang, Huaizhen, Li, Gaocai, Wang, Kun, Yang, Cao. 2023. The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking. In Autophagy, 20, 809-829. doi:10.1080/15548627.2023.2274205. https://pubmed.ncbi.nlm.nih.gov/37876250/

2. Bi, Paul Y, Killackey, Samuel A, Schweizer, Linus, Girardin, Stephen E. 2023. NLRX1: Versatile functions of a mitochondrial NLR protein that controls mitophagy. In Biomedical journal, 47, 100635. doi:10.1016/j.bj.2023.100635. https://pubmed.ncbi.nlm.nih.gov/37574163/

3. Nagai-Singer, Margaret A, Morrison, Holly A, Allen, Irving C. 2019. NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function. In Frontiers in immunology, 10, 2419. doi:10.3389/fimmu.2019.02419. https://pubmed.ncbi.nlm.nih.gov/31681307/

4. Liu, Ye, Kors, Lotte, Butter, Loes M, Florquin, Sandrine, Tammaro, Alessandra. 2023. NLRX1 Prevents M2 Macrophage Polarization and Excessive Renal Fibrosis in Chronic Obstructive Nephropathy. In Cells, 13, . doi:10.3390/cells13010023. https://pubmed.ncbi.nlm.nih.gov/38201227/