31 Wikstrom, J. D. Katzman, S. M. Mohamed, H. Twig, G. Graf, S. A. Heart, E. Molina, A. J. Corkey, B. E. de Vargas, L. M. Danial, N. N. Collins, S. Shirihai, O. S. 2007 Diabetes 56 10 2569-78 Oct 1939-327X (Electronic) 17686943 Ion Channels/deficiency Insulin-Secreting Cells/cytology/drug effects/*physiology Insulin/*secretion Glucose/*pharmacology Cell Culture Techniques Calcium/pharmacology Animals bcl-Associated Death Protein/deficiency Mitochondrial Proteins/deficiency Mitochondrial Membranes/drug effects/*physiology/ultrastructure Microscopy, Confocal Mice, Knockout Mice, Inbred C57BL Mice Membrane Potentials/drug effects/*physiology Male Magnesium/pharmacology Islets of Langerhans/cytology/drug effects/physiology Microscopy Confocal Knockout Inbred C57BL OBJECTIVE: beta-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 beta-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 beta-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 beta-cells reflects a metabolic reservoir recruited by an increased level of fuels and therefore may serve as a therapeutic target. 1R01DK074778/DK/NIDDK NIH HHS/United States1R21DK070303/DK/NIDDK NIH HHS/United States22RO1DK35914/DK/NIDDK NIH HHS/United States5R01HL071629/HL/NHLBI NIH HHS/United StatesP30 NS047243/NS/NINDS NIH HHS/United StatesP41 RR001395/RR/NCRR NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, U.S. Gov't, Non-P.H.S.United States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17686943