On July 6, a research paper entitled “NRF1-mediated mitochondrial biogenesis antagonizes innate antiviral immunity” by a team headed by professor Zhu Yushan from the College of Life Sciences, State Key Laboratory for Medicinal Chemistry and Biology and Interdisciplinary Center of Cell Response of Nankai University was published in The EMBO Journal. The study revealed for the first time that in the case of viral infection, the host participates in the repair of damaged mitochondria by activating the NRF1-dependent mitochondrial biogenesis, thereby inhibiting the production of signaling molecules of mitochondrial damage and preventing excessive activation of innate immunity.

In the preliminary study, Professor Zhu Yushan’s team unexpectedly found that mitochondrial biogenesis is significantly activated during viral infection, and confirmed that this activation depends on nuclear respiratory factor 1 (NRF1). The researchers found that removing NRF1 can block the mitochondrial biogenesis in mouse macrophages, causing severe damage to mitochondria under viral infection, which triggers the leakage of mitochondria-derived reactive oxygen species and immune signaling molecules such as mtDNA, and then induces overactivation of the natural immune response in macrophages. Moreover, in the case of DNA virus infection, TBK1, the core kinase in the innate immune system, will also carry out specific phosphorylation of NRF1 to inhibit the transcriptional activation of TFAM gene, thereby inhibiting the replication and transcription of TFAM-mediated mitochondrial DNA and inducing the cytosol release of mitochondrial DNA under virus infection. Finally, the researchers leveraged Knock-In technology to block the phosphorylation of NRF1 by TBK1 in mice, thereby inhibiting the innate antiviral immune response of the host under DNA virus infection.

This study revealed the regulatory mechanism of mitochondrial biogenesis activated by immunity to viral infection, and identified the key role of NRF1-mediated mitochondrial biogenesis in the regulation of conjugated organelle homeostasis and innate immune response. At the same time, the study analyzed the immune response mechanism dominated by TBK1-NRF1-TFAM-mitochondrial DNA signaling axis under DNA virus infection. These findings are significant in the field of mitochondria and natural immunity, and also provide a new theoretical basis for anti-infection and anti-inflammatory prevention and treatment for targeted mitochondria.

Figure 1: Innate immune response mechanism regulated by mitochondrial biogenesis

Zhao Tian, a doctoral student at the College of Life Sciences of Nankai University, is the first author of the paper, and Professor Zhu Yushan is the corresponding author. The research was supported by Dr. Zhang Jiaojiao, Dr. Lei Hong, Dr. Meng Yuanyuan and Dr. Cheng Hongcheng from the College of Life Sciences. The research also received strong support from partners such as Professor Chen Quan, Professor Shang Yingli, and Professor Hu Gang.

Link to the paper: https://www.embopress.org/doi/full/10.15252/embj.2022113258

(Edited and Translated by Nankai News Team.)