| 1. |
- Wikström, Jakob D., et al.
(författare)
-
Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure
- 2014
-
Ingår i: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 33:5, s. 418-436
-
Tidskriftsartikel (refereegranskat)abstract
- Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE-mediated Drp1 phosphorylation was dependent on Protein Kinase-A (PKA) activity, whereas Opa1 cleavage required mitochondrial depolarization mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold-exposed mice. Mitochondrial uncoupling induced by NE in brown adipocytes was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure. These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Together these data reveal that adrenergically-induced changes to mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.
|
|
| 2. |
- Wikstöm, Jakob, et al.
(författare)
-
What can mitochondrial heterogeneity tell us about mitochondrial dynamics and autophagy?
- 2009
-
Ingår i: International Journal of Biochemistry and Cell Biology. - : Elsevier BV. - 1357-2725 .- 1878-5875. ; 41:10, s. 1914-1927
-
Forskningsöversikt (refereegranskat)abstract
- A growing body of evidence shows that mitochondria are heterogeneous in terms of structure and function. Increased heterogeneity has been demonstrated in a number of disease models including ischemia-reperfusion and nutrient-induced beta cell dysfunction and diabetes. Subcellular location and proximity to other organelles, as well as uneven distribution of respiratory components have been considered as the main contributors to the basal level of heterogeneity. Recent studies point to mitochondrial dynamics and autophagy as major regulators of mitochondrial heterogeneity. While mitochondrial fusion mixes the content of the mitochondrial network, fission dissects the mitochondrial network and generates depolarized segments. These depolarized mitochondria are segregated from the networking population, forming a pre-autophagic pool contributing to heterogeneity. The capacity of a network to yield a depolarized daughter mitochondrion by a fission event is fundamental to the generation of heterogeneity. Several studies and data presented here provide a potential explanation, suggesting that protein and membranous structures are unevenly distributed within the individual mitochondrion and that inner membrane components do not mix during a fusion event to the same extent as the matrix components do. In conclusion, mitochondrial subcellular heterogeneity is a reflection of the mitochondrial lifecycle that involves frequent fusion events in which components maybe unevenly mixed and followed by fission events generating disparate daughter mitochondria, some of which may fuse again, others will remain solitary and join a pre-autophagic pool.
|
|
