About this Research Topic
Mitochondria control innate and adaptive immune responses in health and contribute to diverse pathological conditions. Among these are acute and chronic inflammatory and immune diseases, diabetes, obesity and cancer. By orchestrating energy supply and intracellular signaling pathways, mitochondria direct cellular activation, proliferation and cell death. Supporting their physiologic fidelity is cross-talk between the nuclear and mitochondrial genome interactions, which regulate the quality control mechanisms of mitochondrial biogenesis, fusion, fission and mitophagy. Any imbalance of fidelity disrupts mitochondrial homeostasis. Mitochondria are also a primary intracellular source of reactive oxygen species (mROS). Non-toxic low levels of mROS signal cell activation and deactivation, but excess mROS lead to oxidative stress-induced cellular injury.
Inflammatory stimulation of innate leukocytes drives distinct reprogramming of mitochondrial metabolism and respiration, leading to increased accumulation of major Tricarboxylic Acid (TCA) cycle intermediates including citrate, α-ketoglutarate, succinate, fumarate, malate and oxaloacetate, and generation of additional metabolites such as itaconate. TCA cycle intermediates signal diverse functions in leukocytes including inflammation, epigenetic modifications, antimicrobial functions and cell survival. Citrate and succinate promote inflammation. In contrast, itaconate represses inflammation and has an antimicrobial activity. The itaconate analogue, dimethyl itaconate attenuates inflammatory response in conditions such as psoriasis. 4-octyl itaconate activates Nrf2 pathway and inhibits NLRP3 driven inflammation. Itaconate also represses glycolysis. These newly discovered signaling functions mediated by the TCA cycle metabolites and their derivatives place mitochondria at the center stage of the inflammatory response of leukocytes. Optimal mitochondrial function and TCA cycle metabolites also play critical roles in trained innate immunity mediated protection against infections. Leukocyte mitochondrial dysfunction limits primary infection clearance and increases susceptibility to secondary infections among critically ill patients, such as septic patients. Intracellular signaling pathways regulating optimal mitochondrial number and function in leukocytes involve key molecular mediators such as sirtuins and PGC-1α. Stimulation of mitochondrial biogenesis and augmentation of mitochondrial oxidative bioenergetics improve microbial clearance and sepsis outcomes. The majority of studies have focused on inflammation-induced alterations in mitochondrial function and TCA cycle metabolites in innate leukocytes, while studies in lymphocytes are limited.
Our focus on mitochondria and immunity seeks to increase understanding of the mechanistic link between inflammation, oxidative stress, alterations in TCA cycle metabolites and the molecular pathways regulating mitochondrial function and quality control pathways in leukocytes during inflammatory conditions. We welcome the submission of Original Research articles, Comprehensive Reviews and Mini-Reviews which cover any aspect of innate and adaptive leukocyte mitochondrial function, including, but not limited to the following topics:
• Leukocyte mitochondrial contributions to inflammatory and infectious pathologies.
• Mitochondrial respiration and metabolic reprogramming, and TCA cycle metabolites in inflammatory disease.
• TCA cycle metabolites in regulating the functions of T and B lymphocytes.
• Role of mitochondrial quality control pathways such as biogenesis, fission, fusion and mitophagy in regulating leukocyte functions.
• Mitochondrial reactive oxygen species and antioxidant defense mechanisms in leukocyte responses during inflammation.
• Molecular mechanisms linking inflammation-induced alterations in mitochondrial function and leukocyte responses.
• Evaluating the utility of TCA cycle metabolites as biomarkers in inflammatory conditions.
• Evaluating the therapeutic utility of targeting mitochondrial function to alleviate inflammatory pathologies.
• Mitochondrial function at the interface of immune response and tissue injury
Inflammatory stimulation of innate leukocytes drives distinct reprogramming of mitochondrial metabolism and respiration, leading to increased accumulation of major Tricarboxylic Acid (TCA) cycle intermediates including citrate, α-ketoglutarate, succinate, fumarate, malate and oxaloacetate, and generation of additional metabolites such as itaconate. TCA cycle intermediates signal diverse functions in leukocytes including inflammation, epigenetic modifications, antimicrobial functions and cell survival. Citrate and succinate promote inflammation. In contrast, itaconate represses inflammation and has an antimicrobial activity. The itaconate analogue, dimethyl itaconate attenuates inflammatory response in conditions such as psoriasis. 4-octyl itaconate activates Nrf2 pathway and inhibits NLRP3 driven inflammation. Itaconate also represses glycolysis. These newly discovered signaling functions mediated by the TCA cycle metabolites and their derivatives place mitochondria at the center stage of the inflammatory response of leukocytes. Optimal mitochondrial function and TCA cycle metabolites also play critical roles in trained innate immunity mediated protection against infections. Leukocyte mitochondrial dysfunction limits primary infection clearance and increases susceptibility to secondary infections among critically ill patients, such as septic patients. Intracellular signaling pathways regulating optimal mitochondrial number and function in leukocytes involve key molecular mediators such as sirtuins and PGC-1α. Stimulation of mitochondrial biogenesis and augmentation of mitochondrial oxidative bioenergetics improve microbial clearance and sepsis outcomes. The majority of studies have focused on inflammation-induced alterations in mitochondrial function and TCA cycle metabolites in innate leukocytes, while studies in lymphocytes are limited.
Our focus on mitochondria and immunity seeks to increase understanding of the mechanistic link between inflammation, oxidative stress, alterations in TCA cycle metabolites and the molecular pathways regulating mitochondrial function and quality control pathways in leukocytes during inflammatory conditions. We welcome the submission of Original Research articles, Comprehensive Reviews and Mini-Reviews which cover any aspect of innate and adaptive leukocyte mitochondrial function, including, but not limited to the following topics:
• Leukocyte mitochondrial contributions to inflammatory and infectious pathologies.
• Mitochondrial respiration and metabolic reprogramming, and TCA cycle metabolites in inflammatory disease.
• TCA cycle metabolites in regulating the functions of T and B lymphocytes.
• Role of mitochondrial quality control pathways such as biogenesis, fission, fusion and mitophagy in regulating leukocyte functions.
• Mitochondrial reactive oxygen species and antioxidant defense mechanisms in leukocyte responses during inflammation.
• Molecular mechanisms linking inflammation-induced alterations in mitochondrial function and leukocyte responses.
• Evaluating the utility of TCA cycle metabolites as biomarkers in inflammatory conditions.
• Evaluating the therapeutic utility of targeting mitochondrial function to alleviate inflammatory pathologies.
• Mitochondrial function at the interface of immune response and tissue injury
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