Mitochondrial superoxide signaling contributes to norepinephrine-mediated T-lymphocytecytokine profiles

Adam J. Case, Colton T. Roessner, Jun Tian, Matthew C. Zimmerman

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Norepinephrine (NE) produces multifaceted regulatory patterns in T-lymphocytes. Recently, we have shown that NE utilizes redox signaling as evidenced by increased superoxide (O2•-) causally linked to the observed changes in these cells; however, the source of this reactive oxygen species (ROS) remains elusive. Herein, we hypothesized that the source of increased O2•- in NE-stimulated T-lymphocytes is due to disruption of mitochondrial bioenergetics. To address this hypothesis, we utilized purified mouse splenic CD4+ and CD8+ T-lymphocytes stimulated with NE and assessed O2•- levels, mitochondrial metabolism, cellular proliferation, and cytokine profiles. We demonstrate that the increase in O2•- levels in response to NE is time-dependent and occurs at later points of T-lymphocyte activation. Moreover, the source of O2•- was indeed the mitochondria as evidenced by enhanced MitoSOX Red oxidation as well as abrogation of this signal by the addition of the mitochondrial-targeted O2•--scavenging antioxidant MitoTempol. NE-stimulated T-lymphocytes also demonstrated decreased mitochondrial respiratory capacity, which suggests disruption of mitochondrial metabolism and the potential source of increased mitochondrial O2•-. The effects of NE in regards to redox signaling appear to be adrenergic receptordependent as specific receptor antagonists could reverse the increase in O2•-; however, differential receptors regulating these processes were observed in CD4+ versus CD8+ Tlymphocytes. Finally, mitochondrial O2•- was shown to be mechanistic to the NE-mediated T-lymphocyte phenotype as supplementation of MitoTempol could reverse specific changes in cytokine expression observed with NE treatment. Overall, these studies indicate that mitochondrial metabolism and O2•--mediated redox signaling play a regulatory role in the T-lymphocyte response to NE.

Original languageEnglish (US)
Article numbere0164609
JournalPloS one
Issue number10
StatePublished - Oct 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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