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

C. M. Moshfegh, C. W. Collins, V. Gunda, A. Vasanthakumar, J. Z. Cao, Pankaj Singh, L. A. Godley, Adam Case

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 (O 2 [rad]- ) 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 O 2 [rad]- with no evident changes in hydrogen peroxide (H 2 O 2 ), 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 O 2 [rad]- 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 O 2 [rad]- , 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.

Original languageEnglish (US)
Article number101141
JournalRedox Biology
DOIs
StatePublished - Jan 1 2019

Fingerprint

T-cells
Epigenomics
Superoxides
T-Lymphocytes
Superoxide Dismutase
Lymphocyte Activation
Chemical activation
Metabolism
Oxidation-Reduction
cdc Genes
Peroxynitrous Acid
DNA Methylation
Regulator Genes
Metabolites
Methionine
Hydrogen Peroxide
Zinc
Copper
Up-Regulation
Genes

Keywords

  • Adaptive immunity
  • Apoptosis
  • Cytokines
  • Hydroxymethylation
  • Immune
  • Manganese superoxide dismutase
  • Metabolism
  • Methylation
  • Oxidative stress
  • Proliferation
  • Redox

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry

Cite this

Mitochondrial superoxide disrupts the metabolic and epigenetic landscape of CD4 + and CD8 + T-lymphocytes . / Moshfegh, C. M.; Collins, C. W.; Gunda, V.; Vasanthakumar, A.; Cao, J. Z.; Singh, Pankaj; Godley, L. A.; Case, Adam.

In: Redox Biology, 01.01.2019.

Research output: Contribution to journalArticle

Moshfegh, C. M. ; Collins, C. W. ; Gunda, V. ; Vasanthakumar, A. ; Cao, J. Z. ; Singh, Pankaj ; Godley, L. A. ; Case, Adam. / Mitochondrial superoxide disrupts the metabolic and epigenetic landscape of CD4 + and CD8 + T-lymphocytes In: Redox Biology. 2019.
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