Nedergaard 2017 MiP2017

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Jan Nedergaard
Creatine effect in mitochondria from different tissues.

Link: MiP2017

Nedergaard J, Shabalina IG, Cannon B (2017)

Event: MiP2017

COST Action MITOEAGLE
Creatine, or methyl guanidine-acetic acid, is an endogenously formed molecule that is found largely in skeletal muscle and heart, in both free and phosphorylated forms. Of note, creatine is also found in brain, liver, kidney, and brown and brite/beige adipose tissues. It is well established that in heart and skeletal muscle, creatine plays a key role in transferring high energy phosphoryl groups via phosphocreatine from mitochondria and maintaining a high ATP:ADP ratio by phosphorylation of ADP in myofibrillar, sarcoplasmic reticulum and sarcolemma ion-pump ATPases. What creatine is doing in other (not muscle) tissues is less known. In the present study, we compared the effect of creatine addition to isolated mitochondria from heart, liver, brown and brite/beige adipose tissue.

Mitochondria were isolated from C57Bl/6 mice that were single-caged, acclimated for 2 weeks at 18°C and then at 4°C for at least 4 weeks. Prolonged cold exposure turns inguinal white adipose into UCP1-contaning brite/beige adipose tissue. Oxygen consumption of isolated mitochondria was analyzed with Oroboros O2k-FluoRespirometer.

Creatine (20 mM) added to heart mitochondria after ADP phosphorylation drastically increased oxygen consumption, presumably by ADP released from ATP when high-energy phosphoryl group from ATP was transferred to phosphocreatine. This phenomenon is well described [1] and explained by functional coupling of mitochondrial creatine kinase (sarcomeric isoform) and adenine nucleotide translocase and catalysed transfer of phosphoryl groups from ATP generated by OxPhosph with phosphocreatine production. In liver mitochondria, the enhancing effect of creatine was absent; this is well correlated with tissue distribution of sarcomeric creatine kinase. Brown and brite/beige adipose tissue mitochondria are unique in extremely low capacity of phosphorylation system [2] and the presence of highly active sarcomeric creatine kinase looks incompatible with the low phosphorylation activity. However, we were able to shown creatine-enhancing effects in brown fat mitochondria similarly to heart mitochondria. Creatine effect was observed only under high concentration (15-30 mM). We were not able to demonstrate that low creatine (0.01 mM) enhances respiration in beige-fat mitochondria when ADP is limiting.

Our results show that in the presence of ATP and ADP, high concentration of creatine enhanced oxygen consumption in mitochondria containing the sarcomeric isoform of creatine kinase, independently of high or low OxPhosph capacity.


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


Labels: MiParea: Respiration, mt-Medicine, Pharmacology;toxicology 


Organism: Mouse  Tissue;cell: Heart, Liver, Fat  Preparation: Isolated mitochondria 



HRR: Oxygraph-2k 


Affiliations

Dept Molecular Bioscience, Wenner-Gren Inst, Stockholm Univ, Sweden. - jan.nedergaard@su.se

References

  1. Guzun R, Kaambre T, Bagur R, Grichine A, Usson Y, Varikmaa M, Anmann T, Tepp K, Timohhina N, Shevchuk I, Chekulayev V, Boucher F, Dos Santos P, Schlattner U, Wallimann T, Kuznetsov AV, Dzeja P, Aliev M, Saks V (2015) Modular organization of cardiac energy metabolism: energy conversion, transfer and feedback regulation. Acta Physiol (Oxf) 213: 84-106.
  2. Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV. Cannon B, Nedergaard J (2013) UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep 5: 1196-203.