Adenylate kinase 4 promotes mitochondrial biogenesis for macrophage-mediated defense against listeria monocytogenes 3451

Abstract Description Adenylate kinase 4 (Ak4), located in the mitochondrial matrix, catalyzes the conversion of ATP with AMP into two ADPs, playing a crucial role in maintaining cellular energy homeostasis. While macrophages rely on mitochondria for energy and signaling for immune responses, Ak4 role in mitochondrial function and macrophage activity during bacterial infections is unclear. Here, we show that mitochondrial biogenesis and Ak4 expression are positively correlated in thioglycollate-elicited peritoneal macrophages (TG-pMacs) following Listeria monocytogenes (Lm) infection. Ak4 knockout (KO) TG-pMacs exhibited reduced mitochondrial biogenesis, glycolysis, oxidative phosphorylation (OXPHOS), mitochondrial membrane potential, and reactive oxygen species (ROS), and diminished pro-inflammatory cytokines, chemokines, and bactericidal activity post-Lm infection. Supplementing deoxynucleosides (dNs) to enhance mitochondrial DNA (mtDNA) restored mitochondrial biogenesis in wild-type but not Ak4 KO macrophages. Similarly, Ak4 kinase-dead mutants failed to recover mitochondrial function or bacterial clearance. Mice lacking Ak4 in macrophages (Ak4f/fLysMcre), but not in T cells (Ak4f/fCD4cre), showed increased susceptibility to Lm infection. Ak4 kinase-dead mutant mice were also more sensitive to Lm infection. These findings reveal that Ak4 promotes bacterial clearance by enhancing mitochondrial biogenesis in macrophages via kinase activity, linking mitochondrial function to Immune defense. Funding Sources NSTC-111-2320-B-002 -068 -MY3 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)