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J. Biol. Chem., Vol. 283, Issue 12, 7936-7948, March 21, 2008

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Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells^*

Vasilij Koshkin, Feihan F. Dai, Christine A. Robson-Doucette, Catherine B. Chan, and Michael B. Wheeler¹

From the Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario M5S 1A8 and the Department of Physiology and Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

Involvement of the mitochondrial permeability transition (MPT) pore in early stages of lipotoxic stress in the pancreatic β-cell lines MIN6 and INS-1 was the focus of this study. Both long term (indirect) and acute (direct) effects of fatty acid (FA) application on β-cell susceptibility to Ca²⁺-induced MPT induction were examined using both permeabilized and intact β-cells. Long term exposure to moderate (i.e. below cytotoxic) levels of the saturated FA palmitate sensitized β-cell mitochondria to MPT induced by Ca²⁺. Long term exposure to palmitate was significantly a more efficient inducer of MPT than the unsaturated FA oleate, although upon acute application both caused similar MPT activation. Application of antioxidants, inhibitors of the ceramide pathway, or modifiers of membrane fluidity did not protect β-cell mitochondria from FA exposure. However, significant protection was provided by co-application of the unsaturated FA oleate in a phosphatidylinositol 3-kinase-dependent manner. Characterization of MPT pore opening in response to moderate palmitate treatment revealed the opening of a unique form of MPT in β-cells as it encompassed features of both low and high conductance MPT states. Specifically, this MPT showed solute selectivity, characteristic of a low conductance MPT; however, it affected mitochondrial respiration and membrane potential in a way typical of a high conductance MPT. Activation of the full-size/high conductance form of MPT required application of high levels of FA that reduced growth and initiated apoptosis. These findings suggest that in the β-cell, MPTs can act as both initiators of cell death and as versatile modulators of cell metabolism, depending on the mode of the MPT pore induced.

Received for publication, July 10, 2007 , and in revised form, December 26, 2007.

^* This work was supported in part by Canadian Institutes of Health Research Operating Grant MOP-12898 (to M. B. W. and C. B. C.) and Natural Sciences and Engineering Research Council of Canada Grant 72022734 (to M. B. W. and V. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ Supported by a Canadian Institutes of Health Research investigator award. To whom correspondence should be addressed: Dept. of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-6737; Fax: 416-978-4940; E-mail: michael.wheeler{at}utoronto.ca.

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