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Mitochondrial networking protects beta cells from nutrient -induced apoptosis
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Jan Nedergaard)
2009 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, 2303-2315 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Previous studies have reported that beta-cell mitochondria exist as discrete organelles that exhibit heterogeneous bioenergetic capacity. To date, networking activity, and its role in mediating beta-cell mitochondrial morphology and function, remains unclear. In this article, we investigate beta-cell mitochondrial fusion and fission in detail and report alterations in response to various combinations of nutrients. RESEARCH DESIGN AND METHODS: Using matrix-targeted photoactivatable green fluorescent protein, mitochondria were tagged and tracked in beta-cells within intact islets, as isolated cells and as cell lines, revealing frequent fusion and fission events. Manipulations of key mitochondrial dynamics proteins OPA1, DRP1, and Fis1 were tested for their role in beta-cell mitochondrial morphology. The combined effects of free fatty acid and glucose on beta-cell survival, function, and mitochondrial morphology were explored with relation to alterations in fusion and fission capacity. RESULTS: beta-Cell mitochondria are constantly involved in fusion and fission activity that underlies the overall morphology of the organelle. We find that networking activity among mitochondria is capable of distributing a localized green fluorescent protein signal throughout an isolated beta-cell, a beta-cell within an islet, and an INS1 cell. Under noxious conditions, we find that beta-cell mitochondria become fragmented and lose their ability to undergo fusion. Interestingly, manipulations that shift the dynamic balance to favor fusion are able to prevent mitochondrial fragmentation, maintain mitochondrial dynamics, and prevent apoptosis. CONCLUSIONS: These data suggest that alterations in mitochondrial fusion and fission play a critical role in nutrient-induced beta-cell apoptosis and may be involved in the pathophysiology of type 2 diabetes.

Place, publisher, year, edition, pages
American Diabetes Association , 2009. Vol. 58, 2303-2315 p.
Keyword [en]
mitochondria, beta cells, diabetes
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-39342DOI: 10.2337/db07-1781ISI: 000270776200018OAI: oai:DiVA.org:su-39342DiVA: diva2:319504
Note
11 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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