Biological role of mitochondrial TLR4‐mediated NF‐κB signaling pathway in central nervous system injury

Previous studies suggested that central nervous system injury is often accompanied by the activation of Toll‐like receptor 4/NF‐κB pathway, which leads to the upregulation of proapoptotic gene expression, causes mitochondrial oxidative stress, and further aggravates the inflammatory response to induce cell apoptosis. Subsequent studies have shown that NF‐κB and IκBα can directly act on mitochondria. Therefore, elucidation of the specific mechanisms of NF‐κB and IκBα in mitochondria may help to discover new therapeutic targets for central nervous system injury. Recent studies have suggested that NF‐κB (especially RelA) in mitochondria can inhibit mitochondrial respiration or DNA expression, leading to mitochondrial dysfunction. IκBα silencing will cause reactive oxygen species storm and initiate the mitochondrial apoptosis pathway. Other research results suggest that RelA can regulate mitochondrial respiration and energy metabolism balance by interacting with p53 and STAT3, thus initiating the mitochondrial protection mechanism. IκBα can also inhibit apoptosis in mitochondria by interacting with VDAC1 and other molecules. Regulating the biological role of NF‐κB signaling pathway in mitochondria by targeting key proteins such as p53, STAT3, and VDAC1 may help maintain the balance of mitochondrial respiration and energy metabolism, thereby protecting nerve cells and reducing inflammatory storms and death caused by ischemia and hypoxia. Significance statement Central nervous system diseases (including Alzheimer's disease, Parkinson's disease, etc.) are often accompanied by neuroinflammation, ischemia, and hypoxia, which lead to abnormal apoptosis of nerve cells, but the molecular mechanism is unclear. Previous studies have suggested that the activation of Toll‐like receptor 4/NF‐κB pathway in the cytoplasm triggers mitochondrial oxidative stress and induces apoptosis. In recent years, it has been widely reported that the biological effects of NF‐κB and IκBα in mitochondria are closely related to diseases. The review summarized and revealed that NF‐κB and IκBα regulate key protein signaling pathways such as p53, STAT3, and VDAC1 in mitochondria, and maintain the balance of respiration and energy metabolism in mitochondria. This will provide a basis for the study of the molecular mechanism of central nervous system diseases.