Mitochondrial GTP regulates glucose-stimulated insulin secretion.
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 (DeltaSCS-GTP) reduced glucose-stimulated insulin secretion (GSIS) by 50%, while suppression of the ATP-producing isoform (DeltaSCS-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.
Kibbey
Richard G
RG
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Pongratz
Rebecca L
RL
Romanelli
Anthony J
AJ
Wollheim
Claes B
CB
Cline
Gary W
GW
Shulman
Gerald I
GI
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology; D005947:Glucose / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000032:analysis / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects*; D008954:Models, Biological; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013389:Succinate-CoA Ligases / Q000037:antagonists & inhibitors / Q000235:genetics
D007328:Insulin; D034741:RNA, Small Interfering; D006160:Guanosine Triphosphate; D013389:Succinate-CoA Ligases; D005947:Glucose; D002118:Calcium