Desensitization of Mitochondrial Ca2+ and Insulin Secretion Responses in the Beta Cell*
- From the Division of Clinical Biochemistry, Department of Internal Medicine, University Medical Center, CH-1211 Geneva 4, Switzerland
Abstract
The role of mitochondria in the desensitization of insulin secretion was investigated. In rat pancreatic beta cells, both insulin secretion and mitochondrial [Ca2+] increases were desensitized following two challenges with the mitochondrial substrate methyl succinate. In the beta cell line INS-1, similar results were observed when a 5-min interval separated two 5-min pulses. In contrast, ATP generation monitored in luciferase-expressing INS-1 cells was stimulated to the same extent during both exposures to methyl succinate. Succinate, like α-glycerophosphate, activates the electron transport chain at complex II. As a consequence, the mitochondrial membrane hyperpolarizes, promoting ATP synthesis and Ca2+ influx into the mitochondria through the uniporter. The mitochondrial desensitization was further studied in permeabilized INS-1 cells. Increasing extramitochondrial [Ca2+] from 100 to 500 nm enhanced succinate oxidation 4-fold. At 500 nm Ca2+, 1 mm succinate caused a blunted mitochondrial [Ca2+] increase upon the second, compared with the first, stimulation. These effects were mimicked by α-glycerophosphate, and there was cross-desensitization between the two compounds. Succinate hyperpolarized the mitochondrial membrane during both the first and second applications. This suggests that the uniporter itself, rather than the respiratory chain, is desensitized. These results emphasize the key role of the mitochondria not only in the stimulation of insulin secretion, but also in its desensitization.
Footnotes
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↵* This work was supported by Swiss National Science Foundation Grants 32-32376.91 and 32-49755.96 and by a European Union Network grant (to C. B. W.) through the Swiss Federal Office for Education and Science.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed. Tel.: 41-22-702-55-48; Fax: 41-22-702-55-43; E-mail: claes.wollheim{at}medecine.unige.ch.
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↵2 P. Maechler, E. D. Kennedy, and C. B. Wollheim, unpublished observations.
- Abbreviations:
- [Ca2+]m
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mitochondrial Ca2+concentration
- [Ca2+]c
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cytosolic Ca2+ concentration
- ΔΨm
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mitochondrial membrane potential.
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- Received December 1, 1997.
- Revision received May 8, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
