Mitochondrial ROS Take Central Stage in Immune Regulation

As the powerhouse of the cell for producing adenosine triphosphate (ATP), the “energy currency” for energizing aerobic life, the mitochondrion is also a major source of cellular reactive oxygen species (ROS) production. Cutting-edge research studies over the past few years have uncovered a series of previously unrecognized fundamental biological functions carried out by mitochondrial ROS. Among them is the regulation of immunity by mitochondrial ROS signaling. (First online: Mar 13, 2021) REFERENCES Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 2005; 308(5730):1909–11. doi: https://dx.doi.org/10.1126/science.1106653. Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 2009; 119(21):2789–97. doi: https://dx.doi.org/10.1161/CIRCULATIONAHA.108.822403. Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, et al. Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 2010; 12(6):668–74. doi: https://dx.doi.org/10.1016/j.cmet.2010.11.004. Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014; 515(7527):431–5. doi: https://dx.doi.org/10.1038/nature13909. Nickel AG, von Hardenberg A, Hohl M, Loffler JR, Kohlhaas M, Becker J, et al. Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metab 2015; 22(3):472–84. doi: https://dx.doi.org/10.1016/j.cmet.2015.07.008. Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis. Cell 2015; 163(3):560–9. doi: https://dx.doi.org/10.1016/j.cell.2015.10.001. Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 2016; 167(2):457–70 e13. doi: https://dx.doi.org/10.1016/j.cell.2016.08.064. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011; 472(7344):476–80. doi: https://dx.doi.org/10.1038/nature09973. Geng J, Sun X, Wang P, Zhang S, Wang X, Wu H, et al. Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat Immunol 2015; 16(11):1142–52. doi: https://dx.doi.org/10.1038/ni.3268. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 2013; 38(2):225–36. doi: https://dx.doi.org/10.1016/j.immuni.2012.10.020. Oberkampf M, Guillerey C, Mouries J, Rosenbaum P, Fayolle C, Bobard A, et al. Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells. Nat Commun 2018; 9(1):2241. doi: https://dx.doi.org/10.1038/s41467-018-04686-8. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016; 531(7593):253–7. doi: https://dx.doi.org/10.1038/nature16969. Scharping NE, Rivadeneira DB, Menk AV, Vignali PDA, Ford BR, Rittenhouse NL, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol 2021; 22(2):205–15. doi: https://dx.doi.org/10.1038/s41590-020-00834-9.