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

• Autores: Fernández Sada, Evaristo; Silva Platas, Christian; Villegas, César A.; Rivero, S. L.; Willis, B. C.; García, Noemí; Garza, J. R.; Oropeza Almazán, Yuriana; Valverde, Carlos Alfredo; Mazzocchi, Gabriela; Zazueta, Cecilia; Torre Amione, Guillermo; García Rivas, Gerardo
• Año de publicación: 2014
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Ciencias Médicas; Internal medicine; Endocrinology; Voltage-dependent calcium channel; Stimulation; Isoprenaline; Mitochondrion; Uniporter activity; Uniporter; Intracellular; Biology; Pyruvate dehydrogenase complex
• Institución: Universidad Nacional de La Plata

Background and Purpose: Despite the importance of mitochondrial Ca2+ 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 Ca2+ 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.
Centro de Investigaciones Cardiovasculares