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ß-Cell Mitochondria exhibit membrane potential heterogeneity that can be altered by stimulatory or toxic fuel levels

¹ Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA
² Obesity Research Center, Boston University School of Medicine, Boston, MA, USA
³ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
⁴ Division of Biological Sciences, Endocrine Biology Program, CIIT Centers for Health Research, Research Triangle Park, NC, USA

Correspondence: orian.shirihai{at}tufts.edu

Key Words: Mitochondria • mitochondrial membrane potential • beta cell • PA-GFP • TMRE • heterogeneity

ß-cell response to glucose is characterized by mitochondrial membrane potential ( ) 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 if 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. We show that mitochondria display a wide heterogeneity in and a mV range that is considerably larger than the change in mV induced by fuel challenge. Increasing glucose concentration recruits mitochondria into higher levels of homogeneity, while an in vitro diabetes model results in increased heterogeneity. Exploration of the mechanism behind heterogeneity revealed that temporary changes in of individual mitochondria, ATP-hydrolyzing mitochondria and the uncoupling protein UCP2 are not significant contributors to heterogeneity. We identified BAD, previously implicated in mitochondrial recruitment of glucokinase, as a significant factor influencing the level of heterogeneity. We suggest that mitochondrial heterogeneity in ß-cells reflects a metabolic reservoir that is recruited by increased level of fuels and therefore may serve as a therapeutic target.

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