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

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 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.

SUBMITTER: Moshfegh CM

PROVIDER: S-EPMC6859572 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Moshfegh C M CM Collins C W CW Gunda V V Vasanthakumar A A Cao J Z JZ Singh P K PK Godley L A LA Case Adam J AJ

Redox biology 20190221

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 O<sub ...[more]

PMID: 30819616

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

Publications

Mitochondrial superoxide disrupts the metabolic and epigenetic landscape of CD4<sup>+</sup> and CD8<sup>+</sup> T-lymphocytes.

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