AUTHOR=Arumugam Prabhakar , Chauhan Meghna , Rajeev Thejaswitha , Chakraborty Rahul , Bisht Kanika , Madan Mahima , Shankaran Deepthi , Ramalingam Sivaprakash , Gandotra Sheetal , Rao Vivek TITLE=The mitochondrial gene-CMPK2 functions as a rheostat for macrophage homeostasis JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.935710 DOI=10.3389/fimmu.2022.935710 ISSN=1664-3224 ABSTRACT=

In addition to their role in cellular energy production, mitochondria are increasingly recognized as regulators of the innate immune response of phagocytes. Here, we demonstrate that altering expression levels of the mitochondria-associated enzyme, cytidine monophosphate kinase 2 (CMPK2), disrupts mitochondrial physiology and significantly deregulates the resting immune homeostasis of macrophages. Both CMPK2 silenced and constitutively overexpressing macrophage lines portray mitochondrial stress with marked depolarization of their membrane potential, enhanced reactive oxygen species (ROS), and disturbed architecture culminating in the enhanced expression of the pro-inflammatory genes IL1β, TNFα, and IL8. Interestingly, the long-term modulation of CMPK2 expression resulted in an increased glycolytic flux of macrophages akin to the altered physiological state of activated M1 macrophages. While infection-induced inflammation for restricting pathogens is regulated, our observation of a total dysregulation of basal inflammation by bidirectional alteration of CMPK2 expression only highlights the critical role of this gene in mitochondria-mediated control of inflammation.