Puurand 2018 MiPschool Tromso E2
Event: MiPschool Tromso-Bergen 2018
Compartmentalization of high-energy phosphate carriers between intracellular micro-compartments is a phenomenon that ensures efficient energy use. To connect these sites, creatine kinase (CK) and adenylate kinase (AK) energy-transfer networks, which are functionally coupled to oxidative phosphorylation (OXPHOS), could serve as important regulators of cellular energy fluxes . However, for most tissues the intracellular diffusion restrictions for energy metabolites and accompanying micro-compartmentalization together with energy transport circuits is a relatively unexplored and undervalued area in cellular bioenergetics.
Selective permeabilization of cellular outer membrane and high-resolution respirometry can be used to study functional coupling between CK or AK pathways and OXPHOS in different cells and tissues. Using different oxygraphy protocols the ability of creatine or AMP to stimulate OXPHOS through CK and AK reactions, respectively, is easily observable and quantifiable. Additionally, functional coupling between hexokinase and mitochondria can be investigated by monitoring the effect of glucose on respiration .
The results of our recent study show that the decline in the heart muscle performance is not caused by the changes in the respiratory chain complexes activity but mainly by the decrease in the energy transfer efficiency, especially by the CK pathway. During aging, decline in the CK pathway is the first detectable sign of the alterations in bioenergetics metabolism in 1-year-old (middle-aged model) rat cardiomyocytes while the alterations in the AK pathway are not significant .
In wolframin1 gene knockout (Wfs1KO) mice (a model of diabetes and endoplasmatic reticulum stress) in the oxidative heart muscle the AMP ability to stimulate respiration is higher, while the creatine activated respiration is lower than in control animals. However, in the glycolytic m. rectus femoris the activity of AK pathway shows a slight decrease in comparison to the control. In the oxidative heart muscle of Wfs1KO mice the glucose stimulated respiration is significantly higher than in the control group. These results indicate to significant changes in energy metabolism of adult mice heart and skeletal muscle cells accompanied with Wfs1 deficiency.
In conclusion, systemic functional analysis of changes in cellular phosphotransfer networks may help to explain many pathogenic mechanisms in numerous diseases.
- Lab Chemical Biology, National Inst Chemical Physics Biophysics, Tallinn, Estonia. – [email protected]
- 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 Santos6 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.
- Puurand M, Tepp K, Klepinin A, Klepinina L, Shevchuk I, Kaambre T (2018) Rewiew intracellular energy-transfer networks and high-resolution respirometry: a convenient approach for studying their function. Int J Mol Sci 19:2933.
- Tepp K, Puurand M, Timohhina N, Adamson J, Klepinin A, Truu L, Shevchuk I, Chekulayev V, Kaambre T (2017) Changes in the mitochondrial function and in the efficiency of energy transfer pathways during cardiomyocyte aging. Mol Cell Biochem 432:141–58.
Labels: MiParea: Respiration, Genetic knockout;overexpression
Organism: Mouse Tissue;cell: Heart, Skeletal muscle
HRR: Oxygraph-2k Event: E2