While the role of mitochondrial metabolism in controlling T-lymphocyte activation and function is becoming more clear, the specifics of how mitochondrial redox signaling contributes to T-lymphocyte regulation remains elusive. Here, we examined the global effects of elevated mitochondrial superoxide (O2-) on T-lymphocyte activation using a novel model of inducible manganese superoxide dismutase (MnSOD) knock-out. Loss of MnSOD led to specific increases in mitochondrial O2- with no evident changes in hydrogen peroxide (H2O2), peroxynitrite (ONOO-), or copper/zinc superoxide dismutase (CuZnSOD) levels. Unexpectedly, both mitochondrial and glycolytic metabolism showed significant reductions in baseline, maximal capacities, and ATP production with increased mitochondrial O2- levels. MnSOD knock-out T-lymphocytes demonstrated aberrant activation including widespread dysregulation in cytokine production and increased cellular apoptosis. Interestingly, an elevated proliferative signature defined by significant upregulation of cell cycle regulatory genes was also evident in MnSOD knock-out T-lymphocytes, but these cells did not show accelerated proliferative rates. Global disruption in T-lymphocyte DNA methylation and hydroxymethylation was also observed with increased mitochondrial O2-, which was correlated to alterations in intracellular metabolite pools linked to the methionine cycle. Together, these results demonstrate a mitochondrial redox and metabolic couple that when disrupted may alter cellular processes necessary for proper T-lymphocyte activation.
Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytokines, DNA Methylation, Epigenesis, Genetic, Hydrogen Peroxide, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Mitochondria, Oxidation-Reduction, Oxidative Stress, Signal Transduction, Superoxide Dismutase, Superoxides
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Moshfegh, Cassandra M.; Collins, Christopher W.; Gunda, Venugopal; Vasanthakumar, A.; Cao, J. Z.; Singh, Pankaj K.; Godley, L. A.; and Case, Adam J., "Mitochondrial Superoxide Disrupts the Metabolic and Epigenetic Landscape of CD4" (2019). Journal Articles: Eppley Institute. 30.