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Cell Rep. 2019 Jul 16;28(3):759-772.e10. doi: 10.1016/j.celrep.2019.06.058.

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

Author information

1
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
2
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA; Departments of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06519, USA.
3
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06519, USA.
4
Division of Geriatrics and Gerontology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
5
University of Washington Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
6
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Departments of Medicine, Endocrinology, and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
7
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA; Departments of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06519, USA. Electronic address: richard.kibbey@yale.edu.

Abstract

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.

KEYWORDS:

MIMOSA; PEPCK-M; anaplerosis; insulin secretion; metabolic flux; mitochondrial GTP; oxidative phosphorylation; phosphoenolpyruvate; stable isotope; succinyl-CoA synthetase

PMID:
31315053
DOI:
10.1016/j.celrep.2019.06.058
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