ABSTRACT Mitochondria are metabolic organelles that are essential not only for energy transduction, but also a range of other functions including biosynthesis, ion and metal homeostasis, and signaling. The long-term goal of our laboratory is to better understand how mitochondrial function can adjust cell physiology and fate. A hallmark example of how mitochondria can be repurposed to adjust cell function is observed in macrophages, cells of the innate immune system. Upon activation of pro-inflammatory programs, such as with the bacterial membrane component lipopolysaccharide, rates of mitochondrial ATP production steeply collapse, as mitochondria are reprogrammed to generate signals that amplify the innate immune response. However, many of the same pathways engaged in macrophages during inflammatory activation [e.g. toll- like receptor (TLR) and interferon signaling] are also widely present in many other cell types. While this cytokine- mediated mitochondrial reprograming may be evolutionarily beneficial for host defense, these pathways may be damaging when engaged in non-immune cells, particularly electrically excitable cells hugely reliant on oxidative phosphorylation. Moreover, deleterious cytokine-driven effects on mitochondrial energetics could explain why metabolic dysfunction and low-grade inflammation are coincident in a range of chronic and age-related diseases. Over the next five years, we propose to thoroughly and mechanistically characterize how common cytokine-linked pathways – such as TLR and interferon signaling – rewire mitochondria in a range of cell types. We will define the broader transcriptional programs required for this mitochondrial remodeling using pharmacologic and genetic mouse models. Additionally, the proposal will examine how cytokine-driven changes in core mitochondrial processes (e.g. oxidative phosphorylation, biosynthetic pathways, retrograde signaling, etc.) manifest in altered physiology in cells and ex vivo organoids. By purposefully and systematically defining how cytokines reprogram mitochondrial metabolism, this interdisciplinary program promises to reveal new insights into mitochondrial adaptations to stress as well as crosstalk between metabolism and inflammation. Moreover, efforts to pinpoint the regulatory enzymes and pathways driving these changes can help guide novel therapeutic approaches seeking to restore mitochondrial function in the array of diseases that are associated with enhanced inflammation and rooted in metabolic dysfunction.