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Published online August 8, 2007
Diabetes 56:2569-2578, 2007
DOI: 10.2337/db06-0757
© 2007 by the American Diabetes Association
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ß-Cell Mitochondria Exhibit Membrane Potential Heterogeneity That Can Be Altered by Stimulatory or Toxic Fuel Levels

Jakob D. Wikstrom1, Shana M. Katzman1, Hibo Mohamed1, Gilad Twig1, Solomon A. Graf1, Emma Heart2, Anthony J.A. Molina1, Barbara E. Corkey2, Lina Moitoso de Vargas2, Nika N. Danial3, Sheila Collins4, and Orian S. Shirihai1

1 Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts
2 Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts
3 Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
4 Division of Translational Biology, Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina

Address correspondence and reprint requests to Orian S. Shirihai, Tufts University, Department of Pharmacology and Experimental Therapeutics, 136 Harrison Ave., Boston, MA 02111. E-mail: orian.shirihai{at}tufts.edu

Abbreviations: {Delta}{Psi}, mitochondrial membrane potential; FFA, free fatty acid; FI, fluorescence intensity; GLT, glucolipotoxicity; JC-1, tetrachloro-1,1',3,3'-tetraethylbenzimidazol-carbocyanine-iodide; MeS; mono-methyl-succinate; MTG, MitoTracker Green; OM, oligomycin; PA-GFPmt, matrix-targeted photo-activatable green fluorescent protein; ROS, reactive oxygen species; TMRE, tetramethylrhodamine-ethyl-ester-perchlorate; UCP2, uncoupling protein 2

OBJECTIVE—ß-Cell response to glucose is characterized by mitochondrial membrane potential ({Delta}{Psi}) hyperpolarization and the production of metabolites that serve as insulin secretory signals. We have previously shown that glucose-induced mitochondrial hyperpolarization accompanies the concentration-dependent increase in insulin secretion within a wide range of glucose concentrations. This observation represents the integrated response of a large number of mitochondria within each individual cell. However, it is currently unclear whether all mitochondria within a single ß-cell represent a metabolically homogenous population and whether fuel or other stimuli can recruit or silence sizable subpopulations of mitochondria. This study offers insight into the different metabolic states of ß-cell mitochondria.

RESULTS—We show that mitochondria display a wide heterogeneity in {Delta}{Psi} and a millivolt range that is considerably larger than the change in millivolts induced by fuel challenge. Increasing glucose concentration recruits mitochondria into higher levels of homogeneity, while an in vitro diabetes model results in increased {Delta}{Psi} heterogeneity. Exploration of the mechanism behind heterogeneity revealed that temporary changes in {Delta}{Psi} of individual mitochondria, ATP-hydrolyzing mitochondria, and uncoupling protein 2 are not significant contributors to {Delta}{Psi} heterogeneity. We identified BAD, a proapoptotic BCL-2 family member previously implicated in mitochondrial recruitment of glucokinase, as a significant factor influencing the level of heterogeneity.

CONCLUSIONS—We suggest that mitochondrial {Delta}{Psi} heterogeneity in ß-cells reflects a metabolic reservoir recruited by an increased level of fuels and therefore may serve as a therapeutic target.


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Copyright © 2007 by the American Diabetes Association.