Effects of Increased Mitochondrial DNA Mutation on the Macrophage Response to Listeria Monocytogenes

Abstract

Mitochondria are important for cellular function, and as cells divide, their mitochondria also divide by replicating their DNA. The integrity of mitochondria DNA (mtDNA) replication, carried out by Polymerase G (PolG), is critical for the maintenance of mitochondria and their functions. In this study, mice carrying a mutant PolG, PolGD257A, were used to determine the effect of increased mtDNA mutations on the macrophage population and polarization in response to bacterial and cytokine challenge. It was hypothesized that increased mtDNA mutations will inhibit pathogen clearance by macrophages. To test this hypothesis, the PolGD257A mice were used, along with Listeria monocytogenes (LM) as a model of bacterial infection. Three days post LM infection, the bacterial load and the macrophage population was determined in the spleen and liver of PolGD257A and WT mice. No statistical difference was observed in the bacterial load in the liver or spleen, or in the macrophage population in the spleen of the PolGD257A and WT mice. However, the PolGD257A/D257A mice were associated with a higher percentage of macrophages in the liver during LM infection. Polarization of peritoneal macrophages into classically activated (M1) and alternatively activated (M2) macrophages was also studied in vitro. In a single experiment, increased mtDNA mutations in PolGD257A mice seemed to elicit increased M1 and decreased M2 macrophage polarization. Replication of the experiment is warranted to confirm these results. These experimental findings could lead to a better understanding of the role of the mitochondria and macrophages in infectious disease.