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T Cell Activation-Induced Mitochondrial Hyperpolarization Is Mediated by Ca²⁺- and Redox-Dependent Production of Nitric Oxide ¹

Gyorgy Nagy^*, Agnes Koncz^* and Andras Perl^2,*,

Departments of ^* Medicine and Microbiology and Immunology, State University of New York, College of Medicine, Syracuse, NY 13210

Activation, proliferation, or programmed cell death of T lymphocytes is regulated by the mitochondrial transmembrane potential (_m) through controlling ATP synthesis, production of reactive oxygen intermediates (ROI), and release of cell death-inducing factors. Elevation of _m or mitochondrial hyperpolarization is an early and reversible event associated with both T cell activation and apoptosis. In the present study, T cell activation signals leading to mitochondrial hyperpolarization were investigated. CD3/CD28 costimulation of human PBL elevated cytoplasmic and mitochondrial Ca²⁺ levels, ROI production, and NO production, and elicited mitochondrial hyperpolarization. Although T cell activation-induced Ca²⁺ release, ROI levels, and NO production were diminished by inositol 1,4,5-triphosphate receptor antagonist 2-aminoethoxydiphenyl borane, superoxide dismutase mimic manganese (III) tetrakis (4-benzoic acid) porphyrin chloride, spin trap 5-diisopropoxyphosphoryl-5-methyl-1-pyrroline-N-oxide, and NO chelator carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, mitochondrial hyperpolarization was selectively inhibited by carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (-85.0 ± 10.0%; p = 0.008) and, to a lesser extent, by 2-aminoethoxydiphenyl borane. Moreover, NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate diethylenetriamine elicited NO and ROI production, Ca²⁺ release, transient ATP depletion, and robust mitochondrial hyperpolarization (3.5 ± 0.8-fold; p = 0.002). Western blot analysis revealed expression of Ca-dependent endothelial NO synthase and neuronal NO synthase isoforms and absence of Ca-independent inducible NO synthase in PBL. CD3/CD28 costimulation or H₂O₂ elicited severalfold elevations of endothelial NO synthase and neuronal NO synthase expression, as compared with -actin. H₂O₂ also led to moderate mitochondrial hyperpolarization; however, Ca²⁺ influx by ionomycin or Ca²⁺ release from intracellular stores by thapsigargin alone failed to induce NO synthase expression, NO production, or _m elevation. The results suggest that T cell activation-induced mitochondrial hyperpolarization is mediated by ROI- and Ca²⁺-dependent NO production.

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