Macrophage Anti-bacterial Activity is Controlled by Adenylate Kinase 4-Mediated Mitochondrial DNA Synthesis 2241601

Abstract

Abstract Introduction Macrophage anti-bacterial activity requires mtROS production. Macrophage-specific gene upregulation that participates in mtROS-mediated anti-bacteria process remains unclear. Methods We use Listeria monocytogenes (Listeria) and Salmonella typhimurium (Salmonella) as infection models. Results We showed that Listeria and Salmonella infections in human and mouse macrophages increased mtDNA copy number through which to dictate anti-bacterial activity. Interestingly, adenylate kinase 4 (Ak4) expression was upregulated in macrophages after infection. In vivo, Ak4 KO and macrophage-specific Ak4 KO mice became highly susceptible to bacterial infections. We provide evidence that Ak4 is critical for increased mtDNA synthesis and mitochondrial mass in macrophages after bacterial infection. The biochemical function of Ak4 is to transfer a phosphate group from ATP/GTP to (d)AMP for (d)ADP formation, and the K18A and G89S/A166D mutations abolish this function. Unlike Ak4WT, the expression of these mutants in Ak4 KO mice failed to restore the function of Ak4 in mediating the increase of mtDNA synthesis. Conclusion Our results suggest that induction of Ak4 after infection produces more dADP whose conversion to dATP in mitochondria supports mtDNA synthesis and the subsequent increase of mtROS production. Loss of this metabolic coupling in Ak4 KO macrophages diminishes the anti-bacterial activity. Together, our findings highlight the vital role of Ak4 in macrophage defense against pathogenic bacteria. Funding Source Ministry of Education in Taiwan, National Taiwan University (111L892902 and 112L891702) National Science and Technology Council of Taiwan (111-2320-B-002-068-MY3) Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)