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β-Cell Mitochondria Exhibit Membrane Potential Heterogeneity That Can Be Altered by Stimulatory or Toxic Fuel Levels
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Jan Nedergaard)
2007 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, 2569-2578 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Diabetes Association , 2007. Vol. 56, 2569-2578 p.
Keyword [en]
mitochondria, beta cells, diabetes
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-39341DOI: 10.2337/db06-0757OAI: oai:DiVA.org:su-39341DiVA: diva2:319503
Note
12 authorsAvailable from: 2010-05-18 Created: 2010-05-18 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Mitochondrial form and function in pancreatic β-cells and brown adipocytes
Open this publication in new window or tab >>Mitochondrial form and function in pancreatic β-cells and brown adipocytes
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is focused on the role of mitochondria in pancreatic β-cells and brown adipose tissue (BAT). Two main aspects of mitochondria were explored; mitochondrial functional efficiency and the interrelationship between mitochondrial shape and function.

Mitochondria in β-cells were found to exhibit heterogeneity in mitochondrial membrane potential. This functional diversity decreased when cells were challenged with glucose stimuli, suggesting that at higher fuel levels low-activity mitochondria are recruited into a pool of high-activity mitochondria. Glucolipotoxic conditions increased the functional diversity suggesting that this may be of importance for diabetes pathophysiology.

To examine mitochondrial efficiency in intact islets a high throughput islet respirometry method was developed. Due to increased uncoupling, islets from a diabetic animal model exhibit lower respiratory efficiency. Glucose, free fatty acids and amino acids all decreased respiratory efficiency. A large portion of the respiratory efficiency was mediated by reactive oxygen species and the adenine nucleotide translocase.

In β-cells mitochondria were found to undergo cycles of fusion and fission. During glucolipotoxicity mitochondria fragmented and lost their fusion ability. Knock down of the fission protein Fis1 rescued the β-cells from glucolipotoxic induced cell death. BAT mitochondria also showed fusion and fission. The mitochondrial dynamics proteins Mfn2 and Drp1 were shown to strongly affect BAT mitochondrial morphology. In response to a combination of adrenergic and free fatty acid stimuli mitochondria drastically changed from long filamentous structures to fragmented spheres. Inhibiting fission by the negative form of Drp1 decreased BAT response to adrenergic stimuli by half.

In conclusion, mitochondrial efficiency may be of importance for normal as well as compromised β-cell and islet function. Mitochondrial morphology appears critical for mitochondrial function in β-cells and BAT.

Place, publisher, year, edition, pages
The Wenner-Gren Institute,Stockholm University, 2010. 70 p.
Keyword
mitochondria, beta cells, brown adipose tissue, diabetes, obesity
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-39336 (URN)978-91-7447-095-6 (ISBN)
Public defence
2010-06-14, hörsal Fb107, Frescati backe, Svante Arrhenius väg 21 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.Available from: 2010-05-23 Created: 2010-05-18 Last updated: 2010-08-04Bibliographically approved

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