Mitochondrial dysfunction in patients with SLE

Upstate Medical University, Syracuse NY

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Abstract

DESCRIPTION (provided by applicant): Abnormal T cell activation and cell death underlie the pathology of systemic lupus erythematosus (SLE). Immune responses resulting in activation, proliferation, or programmed cell death are dependent on controlled production of reactive oxygen intermediates (ROI) and ATP in mitochondria. In turn, synthesis of ATP and containment of cell death-inducing factors within the mitochondria are dependent on the mitochondrial transmembrane potential (delta/psi(m)) which is subject to regulation by an oxidation-reduction equilibrium of ROI, pyridine nucleotides (NADH/NAD + NADPH/NADP) and GSH levels. Elevation of delta/psi(m), i.e., mitochondrial hyperpolarization and transient ATP depletion have been identified in our laboratory as early and reversible steps in normal T cell activation and apoptosis. By contrast, T lymphocytes of patients with SLE exhibit persistent mitochondrial hyperpolarization, cytoplasmic alkalinization, increased ROI production, as well as diminished levels of intracellular glutathione and ATP. Oxidative stress affects expression and signaling through the T-cell receptor, cell death receptors, and CD38 as well as activity of redox-sensitive caspases and transcription factors mediating lymphokine production. Mitochondrial dysfunction leading to ATP depletion may be ultimately responsible for diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. We recently discovered that T cell activation-induced mitochondrial hyperpolarization is mediated by Ca2+- and ROI-dependent production of nitric oxide (NO). This proposal is focused on understanding the mechanism of persistent mitochondrial hyperpolarization in lupus T cells. Specific Aim 1 will further characterize the role of mitochondrial signal processing, with an emphasis on delta/psi/(m) production of NO and ROI, cytoplasmic alkalinization, and Ca fluxes with respect to aberrant T cell activation and cell death in patients with lupus and healthy and rheumatoid arthritis controls. Specific Aim 2 will assess functioning of isolated mitochondria and metabolic pathways connected to regulation of delta/psi(m), ROI production, and synthesis of ATP and pyridine nucleotides. Specific Aim 3 will assess coordinate changes in gene expression involved in T-cell activation, apoptosis, and metabolism to delineate pathways contributing to or affected by mitochondrial hyperpolarization in SLE. Specific Aim 4 will systematically validate signaling pathways located upstream and downstream of mitochondrial hyperpolarization and identify signals capable of normalizing mitochondrial dysfunction in lupus T cells. Thus, checkpoints of mitochondrial hyperpolarization could represent novel targets of pharmacological intervention in patients with SLE.