Mitoimmunity: Mitochondria adaptation in pathological and physiological states

Abstract

The biochemical of activities occurring in mitochondria are linked to mitochondria morphology. For example, the spatial segregation of biochemical pathways ultimately controls oxidative phosphorylation and energy generation. Systemic and tissue-derived cues shape mitochondria through fission/fusion events, which orchestrates how mitochondria will function. In the immune system, effector cells, such as macrophages, must rapidly alter their metabolism according to extrinsic cues such as cytokines and microbial products, to acquire different phenotypes and functional states necessary for the downstream function. For example, bacterial activated macrophages can produce nitric oxide to kill pathogens while other macrophages favor wound healing and tissue repair. Activated, macrophages have increased metabolic demands closely linked to mitochondria bioenergetics. In model systems, mitochondrial function is closely linked to mitochondria morphology. Systemic and tissue-derived cues shape mitochondria number and function through fission/fusion events, which orchestrates how mitochondria will function. However, in macrophages, almost nothing is known about the relationships between mitochondrial morphology, their adaptive metabolic functions and how mitochondrial dynamics are linked to immune outcomes. Therefore, the overall goal of this proposal is to determine how mitochondria dynamics regulates macrophage phenotype and function in both on physiological and pathological situations. The proposal is divided into three main objectives. First, we will determine how changes in mitochondria fusion/fission alters macrophage phenotype and function and also the role of nitric oxide in this process and the pathways involved. Second, we will determine how changes in mitochondria fusion/fission alters monocyte/macrophage phenotype and function in humans. Third, we will determine how mitochondria dynamics influences the outcome of infectious (Leishmaniasis) and metabolic (obesity-induced insulin resistance) diseases. This unpaved area of research will bring new insights into the field of immunometabolism to further our knowledge into dynamic mitochondria-mediated regulation of macrophages in comparison to our more detailed understanding of mitochondria dynamics in non-immune cells. This proposal offers new insights into how macrophage mitochondria dynamics regulate the outcomes auto-inflammatory, metabolic and infectious diseases with great potential for patient wellbeing, as macrophage metabolism is linked to virtually every acute and chronic disease. Findings from this proposal could lead to the discovery of still unknown pathways and possibly novel treatments for inflammatory diseases. (AU)