Abstract
Mitochondria are master regulators of metabolism and have emerged as key signalling organelles of the innate immune system. Each mitochondrion harbours potent agonists of inflammation, including mitochondrial DNA (mtDNA), which are normally shielded from the rest of the cell and extracellular environment and therefore do not elicit detrimental inflammatory cascades. Mitochondrial damage and dysfunction can lead to the cytosolic and extracellular exposure of mtDNA, which triggers inflammation in a number of diseases including autoimmune neurodegenerative disorders. However, recent research has revealed that the extra-mitochondrial exposure of mtDNA is not solely a negative consequence of mitochondrial damage and pointed to an active role of mitochondria in innate immunity. Metabolic cues including nucleotide imbalance can stimulate the release of mtDNA from mitochondria in order to drive a type I interferon response. Moreover, important effectors of the innate immune response to pathogen infection, such as the mitochondrial antiviral signalling protein (MAVS), are located at the mitochondrial surface and modulated by the cellular metabolic status and mitochondrial dynamics. In this review, we explore how and why metabolism and innate immunity converge at the mitochondria and describe how mitochondria orchestrate innate immune signalling pathways in different metabolic scenarios. Understanding how cellular metabolism and metabolic programming of mitochondria are translated into innate immune responses bears relevance to a broad range of human diseases including cancer.
Highlights
Metabolism and Innate Immunity Meet at the MitochondriaReviewed by: Damien Arnoult, INSERM U1197 Unité Mixte de Recherche Interactions Cellules Souches-Niches, France María A
Mitochondria are dynamic double-membrane organelles responsible for ATP production, the biosynthesis of macromolecules including lipids, proteins, and nucleotides and for cellular redox status
CMPK2 phosphorylates dCMP to dCDP in the mitochondrial deoxynucleoside triphosphate salvage pathway and is rate limiting for the accumulation of newly synthesised oxidised mitochondrial DNA (mtDNA) in primed macrophages, which stimulates the inflammasome upon exposure to the cytosol (Zhong et al, 2018; Figure 2)
Summary
Reviewed by: Damien Arnoult, INSERM U1197 Unité Mixte de Recherche Interactions Cellules Souches-Niches, France María A. Mitochondria are master regulators of metabolism and have emerged as key signalling organelles of the innate immune system. Mitochondrial damage and dysfunction can lead to the cytosolic and extracellular exposure of mtDNA, which triggers inflammation in a number of diseases including autoimmune neurodegenerative disorders. Recent research has revealed that the extra-mitochondrial exposure of mtDNA is not solely a negative consequence of mitochondrial damage and pointed to an active role of mitochondria in innate immunity. Important effectors of the innate immune response to pathogen infection, such as the mitochondrial antiviral signalling protein (MAVS), are located at the mitochondrial surface and modulated by the cellular metabolic status and mitochondrial dynamics. Understanding how cellular metabolism and metabolic programming of mitochondria are translated into innate immune responses bears relevance to a broad range of human diseases including cancer
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