Importance of mitochodrial [i.e. mitochondrial] glycerol-3-phosphate acyltranferase [i.e. acyltransferase] in T-lymphocyte function and aging
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Aging is associated with immune dysfunction, characterized by reduced Tlymphocyte proliferation ex vivo. One potential mechanism for the reduced proliferation in aged T-lymphocytes is a decreased ratio of membrane glycerophospholipid to cholesterol. Extracting membrane cholesterol does not completely restore T-lymphocyte proliferation, therefore, the goal of this project was to test the novel hypothesis that aged T-lymphocyte proliferative capacity may be reduced, in part, due to suppressed phosphatidic acid (PA) biosynthesis. We show that stimulation and recombinant acylCoA binding protein (ACBP) increase mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT) activity in rat splenic T-lymphocytes and that this effect is blunted in aged T-lymphocytes. Consequently, we wanted to determine the mechanism by which mtGPAT activity is regulated in young and old T-lymphocytes. We show that aged T-lymphocyte mtGPAT activity is not increased by ex vivo stimulation or in vitro phosphorylation with casein kinase 2 (CK2) and protein kinase C theta (PKC θ) as is seen in young T-lymphocytes. A second isoform of mtGPAT, mtGPAT2, has been identified, however, its expression is undetectable in T-lymphocytes, suggesting that at least mtGPAT 1 is responsive to phosphorylation in vitro. Other factors that might influence mtGPAT activity such as reduced mtGPAT protein levels, gene expression or alterations in the soluble acyl-CoA pool were not affected by age or stimulation indicating that posttranslational modification may be the primary mechanism by which mtGPAT activity is regulated in T-lymphocytes. Because aging is associated with both reduced proliferation and reduced mtGPAT1 activity, we hypothesized that young mtGPAT1 knockout mice would have altered glycerophospholipid levels and reduced proliferation ex vivo. We show that mtGPAT1 knockout T-lymphocytes exhibit similar changes seen in aged T-lymphocytes including reduced splenic T-lymphocyte IL-2 secretion and subsequent proliferation, decreased ratio of membrane glycerophospholipid to cholesterol, changes in thymic development, and increased cell death following Tlymphocyte activation. Taken together, these data suggest a novel mechanism by which mtGPAT1 regulates young T-lymphocyte proliferation and indicate that mtGPAT1 may serve as a key target in the age-dependent decline in T-lymphocyte proliferation.