Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential for murine CD4(+) T cell metabolic activation.
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Glycerol-3-phosphate acyltransferase-1 is the first rate limiting step in de novo glycerophospholipid synthesis. We have previously demonstrated that GPAT-1 deletion can significantly alter T cell function resulting in a T cell phenotype similar to that seen in aging. Recent studies have suggested that changes in the metabolic profile of T cells are responsible for defining specific effector functions and T cell subsets. Therefore, we determined whether T cell dysfunction in GPAT-1 (-/-) CD4(+) T cells could be explained by changes in cellular metabolism. We show here for the first time that GPAT-1 (-/-) CD4(+) T cells exhibit several key metabolic defects. Striking decreases in both the oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) were observed in GPAT-1 (-/-) CD4(+) T cells following CD3/CD28 stimulation indicating an inherent cellular defect in energy production. In addition, the spare respiratory capacity (SRC) of GPAT-1 (-/-) CD4+ T cells, a key indicator of their ability to cope with mitochondrial stress was significantly decreased. We also observed a significant reduction in mitochondrial membrane potential in GPAT-1 (-/-) CD4(+) T cells compared to their WT counterparts, indicating that GPAT-1 deficiency results in altered or dysfunctional mitochondria. These data demonstrate that deletion of GPAT-1 can dramatically alter total cellular metabolism under conditions of increased energy demand. Furthermore, altered metabolic response following stimulation may be the defining mechanism underlying T cell dysfunction in GPAT-1 (-/-) CD4(+) T cells. Taken together, these results indicate that GPAT-1 is essential for the response to the increased metabolic demands associated with T cell activation.
author list (cited authors)
Faris, R., Fan, Y., De Angulo, A., Chapkin, R. S., deGraffenried, L. A., & Jolly, C. A.
complete list of authors
Faris, Robert||Fan, Yang-Yi||De Angulo, Alejandra||Chapkin, Robert S||deGraffenried, Linda A||Jolly, Christopher A