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Volume 271, Number 42, Issue of October 18, 1996 pp. 26194-26199
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Mitochondrial DNA Is Required for Regulation of Glucose-stimulated Insulin Secretion in a Mouse Pancreatic Beta Cell Line, MIN6

(Received for publication, May 1, 1996, and in revised form, July 15, 1996)

Aki Soejima , Kimiko Inoue , Daisaku Takai , Motohisa Kaneko ^§ , Hisamitsu Ishihara ^¶ , Yoshitomo Oka and Jun-Ichi Hayashi

From the  Institute of Biological Sciences, University of Tsukuba, Tsukuba, Ibaraki 305, Japan, ^§ Biophysics Division, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104, Japan, ^¶ Third Department of Internal Medicine, University of Tokyo, Hongo, Bunkyou-ku, Tokyo 113, Japan, and  Third Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi 755, Japan

To determine whether mtDNA and mitochondrial respiratory function in pancreatic beta cells are necessary for the phenotypic expression of glucose-stimulated insulin secretion, we used a cultured mouse pancreatic beta cell line, MIN6, and two derivative lines, mtDNA knockout MIN6 (⁰ MIN6) and mtDNA repopulated cybrid MIN6. The MIN6 cells retain the property of glucose-stimulated insulin secretion, but their mtDNA knockout induced the loss of mitochondrial transcription, translation, and respiration activity, without inhibition of transcription of the insulin gene or loss of succinate dehydrogenase activity, indicating that the observed mitochondrial dysfunction in ⁰ MIN6 cells was not due to a cytotoxic side effect derived from the mtDNA knockout. Moreover, the mtDNA depletion also inhibited both the glucose-stimulated increase in the intracellular free Ca²⁺ content and the elevation of insulin secretion. The possibility of the involvement of nuclear genome-encoded factors in this process was excluded by the observation that the missing sensitivity to extracellular glucose stimulation in ⁰ MIN6 cells was restored reversibly by repopulation with foreign mtDNA and isolating cybrid MIN6 clones. Therefore, these findings provide unambiguous evidence for the involvement of the mitochondrial dysfunction induced by mtDNA impairment in developing pathogeneses of some forms of diabetes mellitus.

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