Modulation of mitochondrial respiration rate and calcium-induced swelling by new cromakalim analogues.

Adenosine Triphosphate/metabolism; Animals; Calcium/pharmacology; Cell Line; Cromakalim/analogs & derivatives/pharmacology; Male; Mice; Mice, Inbred C57BL; Mitochondria/drug effects/metabolism; Oxygen Consumption/drug effects; Potassium Channels/agonists/metabolism; Respiratory Rate/drug effects; ATP; Benzopyrans; Cardiomyocytes (H9c2); Cromakalim; ETSmax; K(ATP) channel openers; Mitochondrial Ca(2+) swelling; Oxygen consumption rate (OCR)

Abstract :

[en] A cellular model of cardiomyocytes (H9c2 cell line) and mitochondria isolated from mouse liver were used to understand the drug action of BPDZ490 and BPDZ711, two benzopyran analogues of the reference potassium channel opener cromakalim, on mitochondrial respiratory parameters and swelling, by comparing their effects with those of the parent compound cromakalim. For these three compounds, the oxygen consumption rate (OCR) was determined by high-resolution respirometry (HRR) and their impact on adenosine triphosphate (ATP) production and calcium-induced mitochondrial swelling was investigated. Cromakalim did not modify neither the OCR of H9c2 cells and the ATP production nor the Ca-induced swelling. By contrast, the cromakalim analogue BPDZ490 (1) induced a strong increase of OCR, while the other benzopyran analogue BPDZ711 (2) caused a marked slowdown. For both compounds, 1 displayed a biphasic behavior while 2 still showed an inhibitory effect. Both compounds 1 and 2 were also found to decrease the ATP synthesis, with pronounced effect for 2, while cromakalim remained without effect. Overall, these results indicate that cromakalim, as parent molecule, does not induce per se any direct effect on mitochondrial respiratory function neither on whole cells nor on isolated mitochondria whereas both benzopyran analogues 1 and 2 display totally opposite behavior profiles, suggesting that compound 1, by increasing the maximal respiration capacity, might behave as a mild uncoupling agent and compound 2 is taken as an inhibitor of the mitochondrial electron-transfer chain.

Disciplines :

Biotechnology

Author, co-author :

Mouithys-Mickalad, Ange ; Université de Liège - ULiège > Centre de l'oxygène : Recherche et développement (C.O.R.D.)

Ceusters, Justine ; Université de Liège - ULiège > Dép. clinique des animaux de compagnie et des équidés (DCA) > Chirurgie et clinique chirurgicale des petits animaux

Charif, Mounia

Elmoualij, Benaïssa ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie

Schoumacher, Mathieu

Plyte, Simon

Franck, Thierry ; Université de Liège - ULiège > Centre de l'oxygène : Recherche et développement (C.O.R.D.)

Bettendorff, Lucien ; Université de Liège - ULiège > GIGA Neurosciences - Neurophysiology

Pirotte, Bernard ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique

Serteyn, Didier ; Université de Liège - ULiège > Dép. clinique des animaux de compagnie et des équidés (DCA) > Anesthésiologie gén. et pathologie chirurg. des grds animaux

De Tullio, Pascal ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique

Language :

English

Title :

Modulation of mitochondrial respiration rate and calcium-induced swelling by new cromakalim analogues.

Publication date :

2020

Journal title :

Chemico-Biological Interactions

ISSN :

0009-2797

eISSN :

1872-7786

Publisher :

Elsevier, Amsterdam, Netherlands

Volume :

331

Pages :

109272

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 28 April 2021

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