To gain insight into the regulation of pancreatic β-cell mitochondrial metabolism, the direct effects on respiration of different mitochondrial substrates, variations in the ATP/ADP ratio and free Ca2+ were examined using isolated mitochondria and permeabilized clonal pancreatic β-cells (HIT). Respiration from pyruvate was high and not influenced by Ca2+ in State 3 or under various redox states and fixed values of the ATP/ADP ratio; nevertheless, high Ca2+ elevated pyridine nucleotide fluorescence, indicating activation of pyruvate dehydrogenase by Ca2+. Furthermore, in the presence of pyruvate, elevated Ca2+ stimulated CO2 production from pyruvate, increased citrate production and efflux from the mitochondria and inhibited CO2 production from palmitate. The latter observation suggests that β-cell fatty acid oxidation is not regulated exclusively by malonyl-CoA but also by the mitochondrial redox state. α-Glycerophosphate (α-GP) oxidation was Ca2+-dependent with a half-maximal rate observed at around 300 nM Ca2+. We have recently demonstrated that increases in respiration precede increases in Ca2+ in glucose-stimulated clonal pancreatic β-cells (HIT), indicating that Ca2+ is not responsible for the initial stimulation of respiration [Civelek, Deeney, Kubik, Schultz, Tornheim and Corkey (1996) Biochem. J. 315, 1015–1019]. It is suggested that respiration is stimulated by increased substrate (α-GP and pyruvate) supply together with oscillatory increases in ADP [Nilsson, Schultz, Berggren, Corkey and Tornheim (1996) Biochem. J. 314, 91–94]. The rise in Ca2+, which in itself may not significantly increase net respiration, could have the important functions of (1) activating the α-GP shuttle, to maintain an oxidized cytosol and high glycolytic flux; (2) activating pyruvate dehydrogenase, and indirectly pyruvate carboxylase, to sustain production of citrate and hence the putative signal coupling factors, malonyl-CoA and acyl-CoA; and (3) increasing mitochondrial redox state to implement the switch from fatty acid to pyruvate oxidation.
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September 1996
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Research Article|
September 01 1996
Regulation of pancreatic β-cell mitochondrial metabolism: influence of Ca2+, substrate and ADP
Vildan N CIVELEK;
Vildan N CIVELEK
*Diabetes and Metabolism Unit, Evans Department of Medicine
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Jude T DEENEY;
Jude T DEENEY
*Diabetes and Metabolism Unit, Evans Department of Medicine
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Nicholas J SHALOSKY;
Nicholas J SHALOSKY
*Diabetes and Metabolism Unit, Evans Department of Medicine
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Keith TORNHEIM;
Keith TORNHEIM
*Diabetes and Metabolism Unit, Evans Department of Medicine
†Department of Biochemistry, Boston University Medical Center, Boston, MA 02118, U.S.A.
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Richard G. HANSFORD;
Richard G. HANSFORD
‡Energy Metabolism and Bioenergetics Section, NIA, NIH, Francis Scott Key Medical Center, Baltimore, MD 21224, U.S.A.
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Marc PRENTKI;
Marc PRENTKI
§Molecular Nutrition Unit, Department of Nutrition, University of Montreal, PQ H3C3J7, Canada
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Barbara E. CORKEY
Barbara E. CORKEY
‖
*Diabetes and Metabolism Unit, Evans Department of Medicine
†Department of Biochemistry, Boston University Medical Center, Boston, MA 02118, U.S.A.
‖To whom correspondence should be addressed at: Diabetes and Metabolism Unit, E-224, Boston University School of Medicine, 88 E. Newton Street, Boston, MA 02118, U.S.A.
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Publisher: Portland Press Ltd
Received:
February 12 1996
Revision Received:
April 29 1996
Accepted:
May 15 1996
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1996
1996
Biochem J (1996) 318 (2): 615–621.
Article history
Received:
February 12 1996
Revision Received:
April 29 1996
Accepted:
May 15 1996
Citation
Vildan N CIVELEK, Jude T DEENEY, Nicholas J SHALOSKY, Keith TORNHEIM, Richard G. HANSFORD, Marc PRENTKI, Barbara E. CORKEY; Regulation of pancreatic β-cell mitochondrial metabolism: influence of Ca2+, substrate and ADP. Biochem J 1 September 1996; 318 (2): 615–621. doi: https://doi.org/10.1042/bj3180615
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