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Brown adipocyte activation is characterized by a wave of mitochondrial fission and depolarization that is dependent on β3 receptor stimulation and Drp1, and is characterized by complete, but reversible, arrest of fusion
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Jan Nedergaard)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background and aims:

Mitochondria are dynamic organelles that frequently undergo fusion and fission. Mitochondrial dynamics has been shown to be essential for a variety of cellular functions and its abrogation has been associated with several diseases. However, the role fusion, fission and architecture play in mitochondrial bioenergetics is still not well understood. Brown adipose tissue (BAT) is a mitochondria dense organ that converts cellular fuels into heat by mitochondrial uncoupling. When activated adrenergically, BAT shows a unique increase in mitochondrial respiratory activity. Therefore, BAT may be a good model to study the interdependence between mitochondrial morphology, dynamics and function. To date, mitochondrial dynamics was not studied in BAT. In this study we set out to examine mitochondrial morphology in BAT and test the hypothesis that mitochondrial morphology is of importance for BAT function.

Materials and methods:

BAT was harvested from 3 to 4-week-old wild-type male C57BL6/J mice and from 5-8 day old pups (Mitofusin2 knockout). Brown adipocytes were differentiated in vitro. A LSM 710 laser scanning confocal microscopy (Zeiss) was used for imaging of mitochondrial morphology using several fluorescent dyes and proteins. Oxygen consumption was measured using the XF24 platform (Seahorse Bioscience). The pro fusion protein Mfn2 was knocked out under the AP2 promoter and the pro fission protein Drp1 was inhibited with adenoviral expression of its dominant negative form.


Mitochondria were found to be highly networked and dependent on mitochondrial dynamics proteins. When stimulating cells with a combination of norepinephrine and free fatty acids we found a synergistic response that included a marked increase in oxygen consumption rates and mitochondrial membrane potential (Δψm) depolarization. Somewhat unexpectedly it was also found that mitochondria in parallel underwent a distinct fragmentation. The fragmented mitochondria appeared sphere-like and had dampened fusion; however cells regained normal function as well as mitochondrial morphology and Δψm within 24h.  Interestingly, Δψm depolarized and mitochondria fragmented in a wave-like fashion where depolarization preceded fragmentation. Inhibition of the pro-fission protein Drp1 was found to inhibit the synergistic response, while knock-out of the pro-fusion protein Mfn2 did not. Thus, mitochondrial fission appeared essential for proper BAT function. Finally, we found the synergistic response to go through the β-adrenergic pathway and be dependent on reactive oxygen species but not on Ca++, permeability transition pore or uncoupling protein 1 expression levels.


Taken together, these findings suggest that mitochondrial morphology in general and mitochondrial fission in particular may play an important physiological role in BA. Future studies will reveal if this may represent a therapeutic target for manipulating BAT activity.

Keyword [en]
mitochondria, brown adipose tissue, obesity
National Category
Research subject
URN: urn:nbn:se:su:diva-39344OAI: diva2:319510
Available from: 2010-05-18 Created: 2010-05-18 Last updated: 2010-08-04Bibliographically 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.
mitochondria, beta cells, brown adipose tissue, diabetes, obesity
National Category
Research subject
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)
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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