title: Mn porphyrin regulation of aerobic glycolysis: implications on the activation of diabetogenic immune cells.
abstract: OBJECTIVE
  The immune system is critical for protection against infections and cancer, but requires scrupulous regulation to limit self-reactivity and autoimmunity. Our group has utilized a manganese porphyrin catalytic antioxidant (MnTE-2-PyP(5+), MnP) as a potential immunoregulatory therapy for type 1 diabetes. MnP has previously been shown to modulate diabetogenic immune responses through decreases in proinflammatory cytokine production from antigen-presenting cells and T cells and to reduce diabetes onset in nonobese diabetic mice. However, it is unclear whether or not MnP treatment can act beyond the reported inflammatory mediators. Therefore, the hypothesis that MnP may be affecting the redox-dependent bioenergetics of diabetogenic splenocytes was investigated.
  
  
  RESULTS
  MnP treatment enhanced glucose oxidation, reduced fatty acid oxidation, but only slightly decreased overall oxidative phosphorylation. These alterations occurred because of increased tricarboxylic acid cycle aconitase enzyme efficiency and were not due to changes in mitochondrial abundance. MnP treatment also displayed decreased aerobic glycolysis, which promotes activated immune cell proliferation, as demonstrated by reduced lactate production and glucose transporter 1 (Glut1) levels and inactivation of key signaling molecules, such as mammalian target of rapamycin, c-myc, and glucose-6-phosphate dehydrogenase.
  
  
  METHODS
  This work highlights the importance of redox signaling by demonstrating that modulation of reactive oxygen species can supplant complex downstream regulation, thus affecting metabolic programming toward aerobic glycolysis.
  
  
  CONCLUSIONS
  MnP treatment promotes metabolic quiescence, impeding diabetogenic autoimmune responses by restricting the metabolic pathways for energy production and affecting anabolic processes necessary for cell proliferation.
authors.affiliation: 1 Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children's Hospital of Pittsburgh of UPMC , Pittsburgh, Pennsylvania.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Delmastro-Greenwood
authors.forename: Tatyana
authors.initials: T
authors.lastname: Votyakova
authors.forename: Eric
authors.initials: E
authors.lastname: Goetzman
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Marre
authors.forename: Dana M
authors.initials: DM
authors.lastname: Previte
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Massimo M
authors.initials: MM
authors.lastname: Trucco
authors.forename: Jon D
authors.initials: JD
authors.lastname: Piganelli
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
chemical_list: D000975:Antioxidants; D008665:Metalloporphyrins; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin; D005947:Glucose