Details

Autor(en) / Beteiligte

• Jesinkey, Sean R.
• Madiraju, Anila K.
• Alves, Tiago C.
• Yarborough, OrLando H.
• Cardone, Rebecca L.
• Zhao, Xiaojian
• Parsaei, Yassmin
• Nasiri, Ali R.
• Butrico, Gina
• Liu, Xinran
• Molina, Anthony J.
• Rountree, Austin M.
• Neal, Adam S.
• Wolf, Dane M.
• Sterpka, John
• Philbrick, William M.
• Sweet, Ian R.
• Shirihai, Orian H.
• Kibbey, Richard G.

Titel

Mitochondrial GTP Links Nutrient Sensing to β Cell Health, Mitochondrial Morphology, and Insulin Secretion Independent of OxPhos

Ist Teil von

• Cell reports (Cambridge), 2019-07, Vol.28 (3), p.759-772.e10

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Mechanisms coordinating pancreatic β cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of β cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and β cell health. [Display omitted] •Enhanced mitochondrial GTP (mtGTP) production amplifies insulin secretion•mtGTP regulates PEPCK-M and cytosolic Ca2+, not OxPhos, to trigger insulin secretion•Exuberant secretion and enhanced insulin biosynthesis can coexist without toxicity•mtGTP turnover enhances insulin content, granule docking, and mitochondrial mass Jesinkey et al. report that mitochondrial GTP (mtGTP) is an integrative nutrient sentinel regulating β cell function. Signaling from mtGTP raises calcium independent of oxidative phosphorylation to promote insulin secretion. Without overworking the β cell, mtGTP cycling potentiates insulin secretion, nutrient sensing, and mitochondrial expansion alongside promoting health and increasing insulin reserves.