The role of mitochondrial CLPP protease in the regulation of innate immunity

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Due to its bacterial origin mitochondria contain numerous potent immunostimulatory damage-associated molecular patterns (DAMPs), including hypomethylated mtDNA, dsRNA and formylated proteins, that can activate the innate immune system, type I interferon (IFN-I) in particular. The exposure of cells to mtDNA has long been known to be immunostimulatory and the release of mtDNA into the cytosol can activate several pattern recognition receptors (PPRs) to trigger a variety of innate immune responses. In recent years it was increasingly recognized that besides supporting the antiviral response orchestrated by PRRs, uncontrolled and excessive release of mitochondrial DAMPs contributes to the dysregulated process observed in numerous inflammatory and autoimmune conditions, as well as in ischemic heart disease and cancer. Whilst new evidence in recent studies has revealed more about the role of mitochondria in the modulation of innate immunity, we are left with more questions than answers, and this project proposal aims to answer some of them. Our preliminary data suggest that mtDNA release might be a highly regulated process that does not depend on the level of mitochondrial dysfunction or physical damage. Instead, we show that mitochondrial matrix protease CLPP, part of mitochondrial quality control machinery, guards against the release of mitochondrial DAMPs and the activation of IFN-I response. Furthermore, CLPP deficiency in vivo provides hints for the crosstalk between innate immunity responses and control of systemic metabolism that were previously not investigated. Using a combination of cell and in vivo models we aim to discover molecular mechanisms behind these processes, to precisely map mitochondrial DAMPs and their signalling cascades. Therefore, this project will allow us to understand the housekeeping role of CLPP protease in guarding cells against the release of mitochondrial DAMPS. We believe they will also provide much-needed knowledge of the role of mitochondria in the activation of innate immunity responses in different pathologies, with prospective to uncover potential therapeutic targets.