The Role of Irgm1 in Mitochondrial Dynamics and Metabolism

Abstract

The Immunity-Related GTPases (IRG) are a family of proteins that are induced by interferon gamma and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes, and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections, as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the first chapter, the role of Irgm1 in mitochondrial dynamics is examined. The structural determinants required for Irgm1's mitochondrial localization and mitochondrial fragmentation activity are delineated. In the second and third chapters, we report that uninfected Irgm1-deficient mice to display high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-γ-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1-deficiency drives metabolic dysfunction in macrophages in a manner that is cell autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.