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Shabalina 2017 Abstract MITOEAGLE Barcelona

From Bioblast
COST Action MITOEAGLE

Control of UCP1 activity in brown fat mitochondria.

Link: MitoEAGLE

Shabalina IG, Kalinovich A, Petrovic N, Cannon B, Nedergaard J (2017)

Event: MitoEAGLE Barcelona 2017

COST Action MITOEAGLE

The function of brown adipose tissue (BAT) is the transfer of energy from food into heat. BAT mitochondria contain uncoupling protein-1 (UCP1), the activity of which is rate-limiting for nonshivering thermogenesis. UCP1 is inhibited by GDP experimentally and by cytosolic ATP within brown-fat cells. Fatty acids are able to overcome this inhibition and re-activate UCP1. A kinetic analysis of UCP1-dependent thermogenesis (identified by comparison with mitochondria lacking UCP1) indicates that the interaction between fatty acids and GDP can be fully described as being competitive. As no direct competition between fatty acids and the GDP-binding site exists, the competition is probably functional [1]. We have analyzed the structural requirements for compounds that stimulate UCP1 in GDP-inhibited brown fat-mitochondria. We have found that a wide range of different structures, only vaguely resembling fatty acids, are able to initiate UCP1-dependent (re)activation of mitochondrial thermogenesis. The limitation for fatty acid chain length is 8-10 carbonyl groups. Increased unsaturation does not influence activation. Fatty aldehydes (4-hydroxy-2-nonenal, trans-2-nonenal and all trans retinal) are not active; therefore, the carboxyl group of the activators is absolutely required for their function [2]. Introduction of several carboxyl groups, as in ฮฒ,ฮฒ'-methyl-substituted ฮฑ,ฯ‰-dioic fatty acids (MEDICA 16 and 14), does not significantly diminish their activity. Noticeably, flip-flop-incapable fatty acids (12-hydroxylauric, dodecanedicarboxylic, benzenehexanoic acid) demonstrate UCP1-dependent function as thermogenic (re)activators. Substitution of hydrogen by fluorine in perfluorooctanoic acid (PFOA) improves the UCP1 (re)activation ability as compared with octanoic acid [3]. Until recently, the widely accepted view was that UCP1 activity is strongly correlated with UCP1 content. However, we have found that overexpression of CIDEA (cell death-inducing DNA fragmentation factor alpha-like effector A) led to the inhibition of UCP1 activity, despite preserved content [4]. We observed a similar phenomenon in respiratory chain-deficient brown fat mitochondria from mtDNA mutator mice. It is currently unclear whether the activity of UCP1 is decreased due to e.g. modifications of the UCP1 molecule itself, or to alterations in the environment of the UCP1 molecule (e.g. the composition of the inner mitochondrial membrane).


โ€ข Bioblast editor: Kandolf G โ€ข O2k-Network Lab: SE Stockholm Nedergaard J


Labels: MiParea: Respiration, Exercise physiology;nutrition;life style  Pathology: Obesity  Stress:Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Fat  Preparation: Intact cells, Permeabilized cells, Isolated mitochondria 



HRR: Oxygraph-2k  Event: A3  Labelled by Shabalina IG 

Affiliations

Dept Mol Biosc, Wenner-Gren Inst, Stockholm Univ, Stockholm, Sweden

References

  1. Shabalina IG, Jacobsson A, Cannon B and Nedergaard J (2004) Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids. J Biol Chem 279:38236-48.
  2. Shabalina IG, Petrovic N, Kramarova TV, Hoeks J, Cannon B and Nedergaard J (2006) UCP1 and defense against oxidative stress. 4-Hydroxy-2-nonenal effects on brown fat mitochondria are uncoupling protein 1-independent. J Biol Chem 281:13882-93.
  3. Shabalina IG, Kalinovich AV, Cannon B and Nedergaard J (2016) Metabolically inert perfluorinated fatty acids directly activate uncoupling protein 1 in brown-fat mitochondria. Archives of Toxicology. 90:1117-28.
  4. Fischer AW, Shabalina IG, Mattsson CL, Abreu-Vieira G, Cannon B, Nedergaard J and Petrovic N (2017) UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment. Am J Physiol Endocrinol Metab 312:E72-E87.