Nitric oxide-dependent mitochondrial biogenesis generates Ca2+ signaling profile of lupus T cells.
Abnormal T cell activation and cell death underlie the pathology of systemic lupus erythematosus. Although mitochondrial hyperpolarization (MHP) represents an early and reversible checkpoint of T cell activation and apoptosis, lupus T cells exhibit persistent MHP. NO has recently been recognized as a key signal of mitochondrial biogenesis and mediator of MHP in human T lymphocytes. In this study, we show that persistent MHP was associated with increased mitochondrial mass (+47.7 +/- 2.8%; p = 0.00017) and increased mitochondrial (+21.8 +/- 4.1%; p = 0.016) and cytoplasmic Ca2+ content in T cells from 19 systemic lupus erythematosus patients with respect to 11 control donors (+38.0 +/- 6.4%; p = 0.0023). Electron microscopy revealed that lupus lymphocytes contained 8.76 +/- 1.0 mitochondria, while control donors contained 3.18 +/- 0.28 mitochondria per cell (p = 0.0009). Increased mitochondrial mass in T cells was associated with 2.08 +/- 0.09-fold enhanced NO production by lupus monocytes (p = 0.0023). Activation of T cells through the TCR initiates a biphasic elevation in cytosolic free Ca2+ concentration, a rapid initial peak observed within minutes, and a plateau phase lasting up to 48 h. In response to CD3/CD28 costimulation, rapid Ca2+ fluxing was enhanced while the plateau phase was diminished in lupus T cells. NO-induced mitochondrial biogenesis in normal T cells enhanced the rapid phase and reduced the plateau of Ca2+ influx upon CD3/CD28 costimulation, thus mimicking the Ca2+ signaling profile of lupus T cells. Mitochondria constitute major Ca2+ stores and NO-dependent mitochondrial biogenesis may account for altered Ca2+ handling by lupus T cells.
Nagy
Gyorgy
G
Department of Medicine, State University of New York, College of Medicine, Syracuse 13210, USA.
Barcza
Maureen
M
Gonchoroff
Nick
N
Phillips
Paul E
PE
Perl
Andras
A
D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000494:pharmacology; D017252:CD3 Complex / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007425:Intracellular Membranes / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008564:Membrane Potentials / Q000276:immunology; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D015854:Up-Regulation / Q000276:immunology
D018106:CD28 Antigens; D017252:CD3 Complex; D009569:Nitric Oxide; D002118:Calcium