Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Activation of the Nitric Oxide-Mitochondrial Hyperpolarization-mTOR-Rab4 Signaling Pathway Before Disease Development in Lupus-Prone Mice
Fernandez1, David, Telarico1, Tiffany, Singh2, Ram Raj, Perl1, Andras
Nitric oxide (NO) dependent persistent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing underlie aberrant T-cell activation and death pathway selection in patients with systemic lupus erythematosus. Activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in lupus T cells which in turn promotes expression of HRES-1/Rab4, a small GTPase that regulates recycling and lysosomal degradation of CD4 surface receptors and TCR. Here, we investigated the activity of the NO-MHP-mTOR-Rab4 signaling pathway in lupus-prone mice.
NZB/NZW(F1) and MRL/lpr lupus-prone female mice and age-matched Balb/c/NZW, C57BL/6, MRL, C57BL/6/lpr female control mice were investigated prior to disease manifestations. NO production, mitochondrial transmembrane potential, and recycling of surface receptors were measured by flow cytometry. Expression and phosphorylation of proteins were studied by western blot.
Increased NO production and MHP as well as over-expression of Rab4 and diminished endocytic recycling of CD4 and CD3 were detected at 4-month of age, while the loss of TCR was observed 7-month of age in NZB/NZW(F1) mice. MRL/lpr mice exhibited increased expression of the mitochondrial voltage-dependent anion channel 1(VDAC1) protein and transaldolase (TAL) and Rab4 but not Rab5 as well as increased mTOR activity at 2 months of age. Rab4 expression was also increased in MRL mice.
T cells from lupus-prone mice exhibit mitochondrial dysfunction characterized by increased NO production, MHP, elevated expression of VDAC1 and TAL, as well as increased mTOR activity. Diminished recycling of CD4 and CD3 were associated with elevated expression of Rab4. The results suggest that mitochondrial and endocytic recycling gene expression signatures and activation of the NO-MHP-mTOR-Rab4 signaling pathway are detectable and precede disease development in lupus-prone mice.
To cite this abstract, please use the following information:
Fernandez, David, Telarico, Tiffany, Singh, Ram Raj, Perl, Andras; Activation of the Nitric Oxide-Mitochondrial Hyperpolarization-mTOR-Rab4 Signaling Pathway Before Disease Development in Lupus-Prone Mice [abstract]. Arthritis Rheum 2009;60 Suppl 10 :2016