title: Assessment of mitochondrial dysfunction in lymphocytes of patients with systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is characterized by abnormal activation and cell death signaling within the immune system. Activation, proliferation, or death of cells of the immune system is dependent on controlled reactive oxygen intermediates (ROI) production and ATP synthesis in mitochondria. The mitochondrial transmembrane potential (∆ψ (m)) reflects the energy stored in the electrochemical gradient across the inner mitochondrial membrane which, in turn, is used by F(0)F(1)-ATPase to convert ADP to ATP during oxidative phosphorylation. Mitochondrial hyperpolarization (MHP) and transient ATP depletion represent early and reversible steps in T cell activation and apoptosis. By contrast, T lymphocytes of patients with SLE exhibit elevated ∆ψ (m), i.e., persistent mitochondrial hyperpolarization (MHP), cytoplasmic alkalinization, increased ROI production, as well as diminished levels of intracellular glutathione and ATP. Increased production of nitric oxide has been identified as a cause of MHP and increased mitochondrial biogenesis. Oxidative stress affects signaling through the T cell receptor as well as activity of redox--sensitive caspases. ATP depletion causes diminished activation-induced apoptosis and sensitizes lupus T cells to necrosis. Activation of the mammalian target of rapamycin (mTOR) has recently emerged as a key sensor of MHP and mediator of enhanced Ca(2+) flux in lupus T cells.
authors.affiliation: Department of Medicine, State University of New York, Upstate Medical University, College of Medicine, Syracuse, NY, USA. perla@upstate.edu
authors.forename: Andras
authors.initials: A
authors.lastname: Perl
authors.forename: Robert
authors.initials: R
authors.lastname: Hanczko
authors.forename: Edward
authors.initials: E
authors.lastname: Doherty
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004579:Electron Transport; D057075:Enzyme Assays; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D008213:Lymphocyte Activation / Q000276:immunology; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D008967:Molecular Biology / Q000379:methods*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017382:Reactive Oxygen Species; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D020169:Caspases; D005978:Glutathione