Journal
CELL METABOLISM
Volume 5, Issue 4, Pages 253-264Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2007.02.008
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Funding
- NIDDK NIH HHS [R01 DK049230, U24 DK076169, K08 DK080142, P01 DK-68229, R01 DK071071, R01 DK-71071, U24 DK-76169, P30 DK045735, R24 DK085638, R01 DK040936-18, R01 DK040936, P30 DK-45735, P01 DK068229, U24 DK059635-05, U24 DK059635, P30 DK045735-119001, P01 DK068229-030001, R01 DK-40936] Funding Source: Medline
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Nucleotide-specific isoforms of the tricarboxylic acid (TCA) cycle enzyme succinyl-CoA synthetase (SCS) catalyze substrate-level synthesis of mitochondrial GTP (mtGTP) and ATP (mtATP). While mtATP yield from glucose metabolism is coupled with oxidative phosphorylation and can vary, each molecule of glucose metabolized within pancreatic beta cells produces approximately one mtGTP, making mtGTP a potentially important fuel signal. In INS-1 832/13 cells and cultured rat islets, siRNA suppression of the GTP-producing pathway (Delta SCS-GTP) reduced glucose-stimulated insulin secretion (GSIS) by 50%, while suppression of the ATP-producing isoform (Delta SCS-ATP) increased GSIS 2-fold. Insulin secretion correlated with increases in cytosolic calcium, but not with changes in NAD(P)H or the ATP/ADP ratio. These data suggest a role for mtGTP in controlling pancreatic GSIS through modulation of mitochondrial metabolism, possibly involving mitochondrial calcium. Furthermore, in light of its tight coupling to TCA oxidation rates, mtGTP production may serve as an important molecular signal of TCA-cycle activity.
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