MiP2005: Session 4

Abstract without presentation                                                 Mitochondrial Physiology Network 10.9: 53-54 (2005) - download pdf


Mitochondrial hyperpolarization: a checkpoint of T-cell life, death, and autoimmunity.

Andras Perl, G Nagy, Q Li, J Ward

Division of Rheumatology, Departments of Medicine, Microbiology and Immunology, State University of New York Upstate Medical University, College of Medicine, 750 East Adams Street, Syracuse, NY 13210, USA. - perla@upstate.edu

    Activation, proliferation, and cell death pathway selection of T lymphocytes depend on reactive oxygen intermediates (ROI) production and ATP synthesis which are tightly regulated via the mitochondrial transmembrane potential (∆ψm). Mitochondrial hyperpolarization (MHP) and ATP depletion represent early and reversible steps in T cell activation and apoptosis. By contrast, T lymphocytes of systemic lupus erythematosus (SLE) patients exhibit persistent MHP, cytoplasmic alkalinization, increased ROI production, and ATP depletion that mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Necrotic, but not apoptotic, cell lysates activate dendritic cells and may account for increased interferon-α production and inflammation in lupus patients. MHP is proposed as a key mechanism of pathogenesis and target for pharmacological intervention in SLE. Persistent MHP was associated with increased mitochondrial mass and increased mitochondrial and cytoplasmic Ca2+ content in T cells and enhanced NO production by monocytes of lupus patients. Activation of T cells through the T cell receptor 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 persistent MHP and NO-dependent mitochondrial biogenesis may account for altered Ca2+ handling by lupus T cells. Coordinated changes in expression of genes encoding members of the electron transport chain (ETC) and anti-oxidant defenses underlie mitochondrial dysfunction and dominate the altered gene expression profile of lupus lymphocytes. Members of the ETC may serve as novel target for pharmacological intervention in SLE.

     Supported in part by grants AI 48079 and AI 061066 from the National Institutes of Health.

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Mitochondrial Physiology