| First Author | Zhong G | Year | 2023 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1869 |
| Issue | 8 | Pages | 166820 |
| PubMed ID | 37558010 | Mgi Jnum | J:339700 |
| Mgi Id | MGI:7521653 | Doi | 10.1016/j.bbadis.2023.166820 |
| Citation | Zhong G, et al. (2023) Enhanced glycolysis by ATPIF1 gene inactivation increased the anti-bacterial activities of neutrophils through induction of ROS and lactic acid. Biochim Biophys Acta Mol Basis Dis 1869(8):166820 |
| abstractText | ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein that regulates the activity of F(o)F(1)-ATP synthase. Mice lacking ATPIF1 throughout their bodies (Atpif1(-/-)) exhibit a reduction in the number of neutrophils. However, it remains unclear whether the inactivation of ATPIF1 impairs the antibacterial function of mice, this study aimed to evaluate it using a mouse peritonitis model. Mice were intraperitoneally injected with E. coli to induce peritonitis, and after 24 h, the colonies of E. coli were counted in agarose plates containing mice peritoneal lavage fluids (PLF) or extract from the liver. Neutrophils were analyzed for glucose metabolism in glycolysis following LPS stimulation. Reactive oxygen species (ROS) and lactic acid (LA) levels in neutrophils were measured using flow cytometry and Seahorse analysis, respectively. N-Acetylcysteine (NAC) and 2-Deoxy-d-glucose (2-DG) were employed to assess the role of ROS and LA in neutrophil bactericidal activity. RNA-seq analysis was conducted in neutrophils to investigate potential mechanisms. In ATPIF1(-/-) neutrophils, bactericidal activity was enhanced, accompanied by increased levels of ROS and LA compared to wildtype neutrophils. The augmented bactericidal activity of ATPIF1(-/-) neutrophils was reversed by pretreatment with NAC or 2-DG. RNA-seq analysis revealed downregulation of multiple genes involved in glutathione metabolism, pyruvate oxidation, and heme synthesis, along with increased expression of inflammatory and apoptotic genes. This study suggests that the inactivation of the Atpif1 gene enhances glucose metabolism in neutrophils, resulting in increased bactericidal activity mediated by elevated levels of ROS and LA. Inhibiting ATPIF1 may be a potential approach to enhance antibacterial immunity. |
