Mitochondrial superoxide disrupts the metabolic and epigenetic landscape of CD4+ and CD8+ T-lymphocytes

Redox Biology
C M MoshfeghAdam J Case

Abstract

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...Continue Reading

Methods Mentioned

BETA
flow cytometry
PCR
thermal dissociation
electron paramagnetic resonance
transfection
transgenic

Software Mentioned

Metaboanalyst
ImageJ
Seahorse Wave
ModFit
FlowJo

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