Mitochondrial fidelity and metabolic agility control immune cell fate and function
Michael N. Sack
Michael N. Sack
Published July 30, 2018
Citation Information: J Clin Invest. 2018;128(9):3651-3661. https://doi.org/10.1172/JCI120845.
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Review Series

Mitochondrial fidelity and metabolic agility control immune cell fate and function

Abstract

Remodeling of mitochondrial metabolism plays an important role in regulating immune cell fate, proliferation, and activity. Furthermore, given their bacterial ancestry, disruption in mitochondrial fidelity leading to extravasation of their content initiates and amplifies innate immune surveillance with a myriad of physiologic and pathologic consequences. Investigations into the role of mitochondria in the immune system have come to the fore, and appreciation of mitochondrial function and quality control in immune regulation has enhanced our understanding of disease pathogenesis and identified new targets for immune modulation. This mitochondria-centered Review focuses on the role of mitochondrial metabolism and fidelity, as well as the role of the mitochondria as a structural platform, for the control of immune cell polarity, activation, and signaling. Mitochondria-linked disease and mitochondrially targeted therapeutic strategies to manage these conditions are also discussed.

Authors

Michael N. Sack

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Figure 2

Mitochondria-linked activation of immune pathways.

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Mitochondria-linked activation of immune pathways. Mitochondrial content...
Mitochondrial content and structure can play integral roles in the activation of inflammatory signaling in response to stress effects or viral infections. Extracellular mtDNA can activate NF-κB–driven inflammation via the intracellular TLR9 receptor. Alternatively, released mtDNA can initiate type I IFN signaling in adjacent immune cells. In response to mitochondrial stressors, ROS-damaged mtDNA, mitochondrial ROS, and the release of cardiolipin (CL) from the IMM can activate the NLRP3 inflammasome to promote IL-1β and IL-18 signaling. The loss of mitochondrial integrity with the extrusion of mtDNA can also activate the cGAS/STING pathway and type I IFN signaling. Finally, the mitochondrion functions as a platform for the dimerization of MAVS to activate a combination of NF-κB and IFN regulator signaling in response to viral infections.