Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity

E. Fernández-Sada, C. Silva-Platas, C. A. Villegas, S. L. Rivero, B. C. Willis, N. García, J. R. Garza, Y. Oropeza-Almazán, C. A. Valverde, G. Mazzocchi, C. Zazueta, G. Torre-Amione, G. García-Rivas

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Background and Purpose Despite the importance of mitochondrial Ca 2+ to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca2+ entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca2+ uniporter in an isolated heart model, at baseline and during increased workload following β-adrenoceptor stimulation. Experimental Approach Cardiac contractility, oxygen consumption and intracellular Ca 2+ transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca2+ uniporter activity. Changes in mitochondrial Ca2+ content and energetic phosphate metabolite levels were determined. Key Results The addition of Ru360, a selective inhibitor of the mitochondrial Ca2+ uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7 μM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360. Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca2+-dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca2+ content (2.5-fold). However, in Ru360-treated hearts, this parameter was attenuated. In addition, β-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca2+ handling, PKA or Ca2+/calmodulin-dependent PK signalling. Conclusions and Implications Inhibition of the mitochondrial Ca2+ uniporter decreases β-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca2+ uniporter activity.

Original languageEnglish (US)
Pages (from-to)4207-4221
Number of pages15
JournalBritish Journal of Pharmacology
Volume171
Issue number18
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Pharmacology

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