Abstract
Abstract Nitric oxide (NO) dependent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing underlie aberrant T cell activation in Systemic Lupus Erythematosus. Activity of mTOR, which senses the mitochondrial membrane potential, is increased in lupus T cells, which promotes HRES-1/Rab4 expression. Rab4 overexpression enhances recycling and lysosomal degradation of immune synapse components, including CD4 and TCRζ. We investigated activity of the NO-MHP-mTOR-Rab4 signaling pathway in lupus-prone mice. Overexpression of Rab4 and loss of TCRζ were detected prior to disease onset of NZB/NZW (F1) mice at 5 months. Increased NO production, mitochondrial transmembrane potential, and mitochondrial mass were present after disease onset at 11 months. MRL/lpr mice exhibited increased expression of the mitochondrial voltage-dependent anion channel 1(VDAC1) protein, transaldolase (TAL), Rab4, mTOR activation, and enhanced CD3 and CD4 recycling at 2-3 months, prior to disease development. In conclusion, lupus-prone mice exhibit mitochondrial dysfunction, with increased NO production, MHP, elevated expression of VDAC1 and TAL, and mTOR activation. Increased Rab4 expression was associated with enhanced endocytic recycling of CD4 and CD3. The results suggest that activation of the NO-MHP-mTOR-Rab4 signaling pathway is detectable and precedes disease onset in lupus-prone mice.
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